Process for the Preparation of and Crystalline Forms of Optical Enantiomers of Modafinil

ABSTRACT

The invention relates to a polymorphic form of (−)-modafinil that produces a powder X-ray diffraction spectrum comprising intensity peaks corresponding to interplanar spacings of about 9.45, 7.15, 5.13, 4.15 and 3.67 Å, and a process for the preparation thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.11/474,859, filed Jun. 26, 2006, which is a continuation of U.S.application Ser. No. 10/539,918, which was the National Stage ofPCT/FR2003/003799, filed Dec. 18, 2003, which claims priority to FrenchApplication No. 0216412, filed Dec. 20, 2002. The foregoing applicationsare incorporated herein by reference in their entireties, for allpurposes.

FIELD OF THE INVENTION

The invention relates to a process for obtaining crystalline forms ofthe enantiomers of modafinil, and the crystalline forms which it ispossible to obtain according to this process.

The invention also relates to a new process for the preparation ofoptical enantiomers of modafinil from (±) modafinil acid.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 4,177,290 describes modafinil in racemic form, also knownas (±) 2-(benzhydrylsulphinyl)acetamide or (±)2-[(di-phenylmethyl)sulphinyl]acetamide, as a compound having propertiesof stimulating the central nervous system.

U.S. Pat. No. 4,927,855 describes the two optical enantiomers ofmodafinil. More particularly it describes the laevorotatory enantiomerand its use as an antidepressant or stimulant agent in the treatment ofhypersomnia and disorders associated with Alzheimer's disease. Theprocess for the preparation of the two optical enantiomers of modafinilfrom (±) modafinil acid or (±)-benzhydrylsulphinylacetic acid describedin this document is illustrated in the following synthesis diagram:

This process comprises carrying out resolution of the opticalenantiomers of (±) modafinil acid in a first stage via the formation ofdiastereoisomers with the optically active agent α-methylbenzylamine.

The (−)-α-methylbenzylamine-(−)-benzhydrylsulphinyl acetate is thenconverted to (−)-benzhydrylsulphinylacetic acid by acid hydrolysis. Thelatter is esterified in the presence of dimethyl sulphate and thenconverted to amide in the presence of ammonia (gas). The (−) or l(laevorotatory) enantiomer of modafinil is obtained through this processwith an overall yield of 5.7% in relation to the (±) modafinil acid,calculated on the basis of the yields corresponding to each stage.

SUMMARY OF THE INVENTION

The term “enantiomer” refers to stereoisomer molecules which arenon-superimposable mirror images of each other. Enantiomers aretypically designated using either (+) and (−) or (d) and (l), whichindicates optical rotating power in the chiral centre.

Stereoisomerism may also be denoted by either (D) or (L) or by (R) and(S), these being descriptive of the absolute configuration.

In what follows the laevorotatory enantiomer of modafinil will bereferred to without distinction as the l or (−) enantiomer, and thedextrorotatory enantiomer will for its part be referred to as the d or(+) enantiomer.

A process through which different crystalline forms of the opticalenantiomers of modafinil can be obtained has now been discovered. Morespecifically the inventors have shown that the crystalline form obtainedmainly depends on the nature of the crystallisation solvent used.

For the purposes of this description the term “crystalline form” refersto either a polymorphic form or a solvate, without distinction.

By “polymorphic form” is meant an organised structure involving onlymolecules of the solute, having a characteristic crystalline signature.

The term “solvate” relates to an organised structure having acharacteristic crystalline signature which involves both molecules ofsolute and molecules of solvent. Solvates having one molecule of solutefor one molecule of solvent are called true solvates.

Furthermore the inventors have shown that l-modafinil and d-modafinilprepared according to the conditions described in U.S. Pat. No.4,177,290 are obtained in the form of one polymorphic form described asform I, which corresponds to the thermodynamically most stablepolymorphic form under normal temperature and pressure conditions.

Form I has the X-ray diffraction spectrum below in which d representsthe interplanar spacing and the ratio (I/Io) the relative intensity.

CRL 40982 FORM I 2 Theta (degrees) d (Å) I/Io (%) 9.8 13.40 32 15.4 8.5487 20.8 6.34 24 26.4 5.01 14 28.3 4.68 19 28.7 4.62 16 29.9 4.44 45 31.14.27 100 31.6 4.20 23 32 4.15 14 33.1 4.02 78 33.4 3.98 84 34.1 3.90 1635.1 3.80 15 39 3.43 22 Diffractometer: Miniflex Rigaku (Elexience)

The crystalline forms of a given compound generally have physical,pharmaceutical, physiological and biological properties which differfrom each other very sharply.

In this respect the crystalline forms of optically active modafinil, inparticular the polymorphic forms, are of interest in that they havedifferent and advantageous properties in comparison with form I.

According to another aspect, a new process for the preparation of theoptical enantiomers of modafinil from (±)-modafinil acid has now beendiscovered, and this process can be used to isolate each enantiomer inyields and with an optical purity which are markedly superior to thosedescribed in U.S. Pat. No. 4,927,855.

In a particularly advantageous fashion a process for resolution of thetwo optical enantiomers of (±)-modafinil acid by preferentialcrystallisation, which is advantageously applicable to the preparationscale, has now been developed.

This process for the resolution of (±)-modafinil acid has manyadvantages:

-   -   it avoids the use of a costly chiral intermediate whose further        preparation involves losses which are rarely less than 10% (De        Min., M., Levy, G. and Michwater J.-C., 1988, J. Chem. Phys. 85,        603-19),    -   the two enantiomers are obtained directly, contrary to the        method which makes use of conventional resolution through the        formation of diastereoisomer salts,    -   the yield is theoretically quantitative as a result of        successive recycling of the mother liquors,    -   Purification of the crude enantiomer crystals is easy.

The invention therefore aims to provide a process of preparation forcrystalline forms of the enantiomers of modafinil.

The invention also aims to provide a new process for preparation of theoptical enantiomers of modafinil, and in particular the laevorotatoryenantiomer of modafinil.

DETAILED DESCRIPTION OF THE INVENTION

Process for the Preparation of L-Modafinil Polymorphs

These objects and others are accomplished by this invention whichrelates more particularly, in a first aspect, to a process for thepreparation of crystalline forms of the optical enantiomers ofmodafinil, comprising the following stages:

-   -   i) dissolving one of the optical enantiomers of modafinil in a        solvent other than ethanol,    -   ii) crystallising the said enantiomer of modafinil, and    -   iii) recovering the crystalline form of the said enantiomer of        modafinil so obtained.

For the purposes of this invention, the solvent used in stage i) of theprocess, also referred to as the “recrystallisation solvent”, is asolvent capable of bringing about crystallisation of the said opticalenantiomer of modafinil, preferably at atmospheric pressure. In otherwords it comprises any solvent A which with at least one of theenantiomers is capable of forming at a given pressure

-   -   in a first temperature and concentration domain, a monophase        system comprising at least one of the enantiomers in dilute        solution in solvent A,    -   in a second temperature and concentration domain which is not        the same as the former, a second two-phase system comprising        crystals of the said enantiomer in the presence of saturated        solution, the two domains being separated from each other by the        solubility curve of the said enantiomer T (° C.)=f (enantiomer        concentration) at the pressure considered.

In general the crystallisation in stage ii) comprises changing from themonophase system to the two-phase system by varying the temperature andconcentration.

By way of a non-restrictive illustration of solvents which may besuitable for the recrystallisation process according to the inventionmention may in particular be made of alcoholic solvents, carboxylic acidester solvents, ether solvents, chlorinated solvents, aromatic solvents,and lower aliphatic ketone solvents. Other solvents are for example,carboxylic acid solvents, aprotic polar solvents, alicyclichydrocarbons, aliphatic hydrocarbons, carbonates, heteroaromatics andwater.

Among the alcoholic solvents mention may be made in particular of loweralkyl alcohols such as methanol, ethanol, propanol, isopropanol,butanol, isobutanol, 2-methyl-2-pentanol, 1,2-propanediol and t-amylalcohol, with methanol, propanol and isopropanol being particularlypreferred.

Among solvents of the carboxylic acid ester type mention may be made inparticular of alkyl acetates such as methyl acetate, ethyl acetate,n-propyl acetate, isopropyl acetate, n-butyl acetate and alkyl formatessuch as ethyl formate, with ethyl acetate being particularly preferred.

Useful ether recrystallisation solvents are diethylether,tetrahydrofuran (THF), dioxan, dibutylether, isopropyl ether,t-butylmethylether and tetrahydropyran, with tetrahydrofuran beingparticularly preferred.

Among the chlorinated solvents mention may be made of chlorinatedhydrocarbons, in particular chloroform, 1,2-dichloroethane,dichloromethane and chlorinated aromatics such as chlorobenzene.

As examples of aromatic solvents mention may be made of ortho, meta, andpara xylene or a mixture of ortho, meta and para xylene, methoxybenzene,nitrobenzene, trifluorotoluene and toluene, with ortho, meta and paraxylene being particularly preferred.

Useful ketone solvents are solvents such as acetone, methylethylketone,methylisobutylketone, butan-2-one, cyclopentanone, isobutylmethylketone,2-pentanone, 3-pentanone.

As an example of a carboxylic acid solvent, mention may be made inparticular of acetic acid.

By way of an example of a heteroaromatic solvent, mention may be made inparticular of pyridine.

Examples of aprotic polar solvents are in particular acetonitrile,propionitrile, 4-methylmorpholine, N,N-dimethylacetamide, nitromethane,triethylamine, N-methyl-pyrrolidone (NMP).

Examples of aliphatic hydrocarbons are in particular heptane,2,2,4-trimethylpentane.

Examples of alicyclic hydrocarbons are in particular cyclopentane,cyclohexane.

Examples of carbonates are in particular alkyl carbonates such asdimethyl carbonate.

According to a preferred embodiment of the process according to theinvention the crystallisation solvents are selected from acetone,methanol, 1-4 dioxan, ethyl acetate, mixtures of ortho, meta, paraxylene, isopropanol, n-propanol, dimethyl carbonate, tetrahydrofuran,chloroform and methylethylketone, water and alcohol/H₂0 mixtures.

Thus, crystalline forms of the optical enantiomers of modafinil can beobtained by recrystallisation of the enantiomers in particular solvents,where the nature and possibly the conditions of crystallisation mainlydetermine the type of crystalline form obtained.

Through its interaction with functional groups and electron-attractingor electron-donor substituents the recrystallisation solvent can in factencourage certain molecular arrangements which give rise to a particularcrystalline form under given crystallisation conditions.

Generally the recrystallisation solvent used in stage i) is heated, inparticular under reflux, until the optical enantiomer of modafinil iscompletely dissolved in the solvent. Although the concentration of theoptical enantiomer of modafinil in stage i) is not a critical factor forthe crystallisation, it is however preferable to work in the presence ofa concentration of optical enantiomer of modafinil which is close to thesaturation concentration in the recrystallisation solvent in question.

According to one embodiment the optical enantiomer of modafinil isdissolved by heating the solvent under reflux and an additional quantityof the said optical enantiomer is then added in fractions in such a wayas to achieve saturation. Additional solvent may be added to ensurecomplete dissolution.

According to another embodiment the optical enantiomer of modafinil issuspended in the solvent heated under reflux and an additional quantityof solvent is then added in fractions so as to obtain a homogeneoussolution and thus achieve saturation.

The process of crystallisation of the optical enantiomer of modafinil instage ii) may be accelerated using techniques known to those skilled inthe art, namely cooling of the solution, evaporation of some of thesolvent, the addition of an antisolvent or seeding the solution withcrystals of optically active modafinil having the same crystalline formas that desired. Most commonly the mixture is stirred continuallythroughout the crystallisation process so as to obtain a homogeneoussuspension and rapid renewal of the mother liquor around eachcrystallite.

The crystallisation process in the process according to the inventionmay be carried out under thermodynamic or kinetic conditions.

For the purposes of this description, by “crystallisation underthermodynamic conditions” is meant crystallisation performed underconditions in which equilibrium is maintained between the homogeneoussolution and the saturated solution in the presence of crystals of l- ord-modafinil.

By way of example, a thermodynamic crystallisation may be performed byslowly cooling the solution obtained in stage i), typically by allowingthe solution to cool to ambient temperature or by applying a rate ofcooling or a cooling gradient which is preferably less than or equal to0.75° C./min, more preferably to 0.6° C./min and more preferably to 0.5°C./min.

By “crystallisation performed under kinetic conditions” for the purposesof this description is meant a crystallisation in which equilibriumbetween the homogeneous solution and the saturated solution in thepresence of crystals of d- or l-modafinil is suddenly displaced towardsthe latter two-phase domain, i.e. towards the formation of crystals.

By way of illustration, a crystallisation which is said to be kineticcan be performed in particular by rapid cooling, for example byimplementing a cooling gradient of 300° C./min, or by precipitationthrough the addition of an antisolvent to the solution obtained in stagei).

By way of an illustrative and non-restrictive example these two types ofthermodynamic or kinetic crystallisation are effected in thisdescription by slow or rapid cooling.

Of course any other technique of crystallisation such as evaporation ofthe solvent or precipitation which would make it possible for kineticand/or thermodynamic conditions to obtain also falls within the scope ofthe process according to the invention.

Thus according to a particular embodiment the crystallisation in stageii) may be performed by precipitation, possibly in the presence of seedcrystals of the desired crystal form.

The inventors have also shown that some solvents can give rise todifferent crystalline forms, more specifically to polymorphic forms,according to whether the crystallisation is performed under kinetic orthermodynamic conditions.

According to a particularly advantageous embodiment crystallisationcomprises cooling of the solution obtained in stage i).

As applicable, in a first mode, cooling is rapid and generallycorresponds to quenching of the solution obtained in stage i) in a bathat a temperature at or below 0° C. such as a bath of ice water for asufficient time to permit complete crystallisation of the solution, oragain cooling with a temperature gradient of for example between −1° C.and −5° C./min.

According to a second embodiment cooling is slow. In this context thesolution is generally allowed to cool from the reflux temperature of thesolvent to ambient temperature or the solution is cooled with a coolinggradient preferably between −0.1° C./min and −0.8° C./min, and morepreferably close to −0.5° C./min, generally down to a temperature of 15°to 20° C.

Among the preferred combinations of solvents/antisolvents according tothe invention mention may be made in particular of the combinationswater/acetone, acetonitrile/water, ethanol/water, methanol/water, aceticacid/water.

Finally the crystalline forms of the optical enantiomers of modafinilcan be isolated using conventional methods such as filtration andcentrifuging.

By way of a non-restrictive illustration the process of preparationaccording to the invention is more particularly implemented using thelaevorotatory enantiomer of modafinil.

According to a particular embodiment the crystalline form obtainedaccording to this process is a polymorphic form.

In this respect it will be noted that in general each of the (l) and (d)enantiomers of a given chemical compound yield crystalline forms, inparticular polymorphic forms, having powder X-ray diffraction spectrawhich are identical when they are recrystallised under the sameexperimental conditions.

In this respect reference should be made in particular to the work of J.Bernstein <<Polymorphism in molecular crystals>> 2002, University Press,Oxford, UK, and the publication by G. Coquerel, Enantiomer, 2000; 5(5):481-498, Gordon and Breach Science Publishers.

In this respect the dextrorotatory form, whose X-ray diffraction spectrafor the crystalline forms are identical to those of the laevorotatoryform described below and vice versa, forms part of the invention.

In what follows the polymorphic forms designated forms I, II, III, IVand V also cover the CRL 40982 forms I, II, III, IV, V obtained from thelaevorotatory enantiomer and the CRL 40983 forms I, II, III, IV, Vobtained from the dextrorotatory enantiomer.

Form I

In this context, the process using a solvent selected from acetone,ethanol, 1-4 dioxan, ethyl acetate and mixtures of ortho, meta and paraxylene, and a stage of crystallisation by slow cooling leads to theacquisition of form I or CRL 40982 form I.

The process using a solvent selected from methanol, water oralcohol/water mixtures, in particular methanol/water and ethanol/water,and a stage of crystallisation by rapid cooling leads to the acquisitionof form I or CRL 40982 form I.

According to another equally preferred variant of the invention, theprocess using methanol and a stage of crystallisation by precipitationthrough the addition of cold water as an antisolvent for methanol leadsto form I.

Form II

According to another embodiment of the invention, the process using asolvent in stage i) selected from isopropanol, ethyl acetate,n-propanol, or ethanol denatured with toluene and a stage ofcrystallisation by rapid cooling leads to a polymorphic form describedas Form II or CRL 40982 form II.

According to a variant of the process form II can also be obtained byslow cooling from isopropanol.

It may also be commented that the production of form II from isopropanoldoes not depend on the conditions of crystallisation (thermodynamic orkinetic).

Form III

According to another variant of the process according to the inventionthe solvent used in stage i) is acetone, and crystallisation stage ii)comprises rapid cooling, this apparently leading to acquisition of apolymorphic form described as form II or CRL 40982 form III.

Form IV

As a variant of the process according to the invention, the solvent usedin stage i) is selected from tetrahydrofuran, chloroform andmethylethylketone, and crystallisation stage ii) comprises slow coolingof the solution, as a result of which a polymorphic form described asform IV or CRL 40982 form IV is obtained.

Depending upon the nature of the solvent used, the process forrecrystallisation of the optical enantiomers of modafinil can give riseto the production of solvates.

Form V

As a variant of the process according to the invention the solvent usedin stage i) is selected from 2-pentanone and tetrahydrofuran, andcrystallisation stage ii) comprises slow cooling of the solution in2-pentanone and rapid cooling in THF, as a result of which a polymorphicform described as form V is obtained.

Dimethyl Carbonate Solvate

Thus according to a particular embodiment of the invention, when thesolvent used in stage i) is dimethyl carbonate and crystallisationconsists of slow cooling, a dimethyl carbonate (−)-modafinil solvate isobtained.

Acetic Acid Solvate

According to a particular embodiment of the invention, when the solventused in stage i) is acetic acid and crystallisation consists of a rapidor slow cooling, an acetic acid solvate is obtained.

Polymorphic Forms of (−)-Modafinil

The invention also relates to the polymorphic form of the laevorotatoryenantiomer of modafinil described as CRL 40982 form II, characterised inthat it produces an X-ray diffraction spectrum comprising intensitypeaks for the interplanar spacings: 11.33, 8.54, 7.57, 7.44, 4.56, 3.78,3.71 Å, the intensity peaks corresponding to the interplanar spacings of8.54, 7.57, 7.44, 4.56, 3.78, 3.71 Å being particularly characteristic.

More specifically the X-ray diffraction spectrum below, in which drepresents the interplanar spacing and I/Io the relative intensity:

CRL 40982 FORM II 2 Theta (degrees) d (Å) I/Io (%) 11.6 11.33 54 15.48.54 58 17.4 7.57 41 17.7 7.44 34 23.3 5.67 19 24.8 5.33 26 27.4 4.83 1928.9 4.59 36 29.1 4.56 97 29.8 4.45 23 32.8 4.05 29 34.3 3.88 23 35.33.78 100 35.9 3.71 40 40.1 3.34 21 47.7 2.83 20 53.7 2.53 32Diffractometer: Miniflex Rigaku (Elexience)

The invention also relates to the polymorphic form of the laevorotatoryenantiomer of modafinil described as CRL 40982 form III, characterisedby an X-ray diffraction spectrum incorporating intensity peaks at thefollowing interplanar spacings d: 13.40, 12.28, 8.54, 7.32, 6.17, 5.01,4.10, 3.97, 3.42, 3.20 Å, and the interplanar spacings: 12.28, 8.54,5.01, 4.10, 3.97, 3.42, 3.20 Å corresponding to the most characteristicintensity peaks.

In this context the invention relates more particularly to form III of(−)-modafinil which produces the following X-ray diffraction spectrum inwhich d represents the interplanar spacing and I/Io the relativeintensity:

CRL 40982 FORM III 2 Theta (degrees) d (Å) I/Io (%) 9.8 13.40 40 10.712.28 39 15.4 8.54 100 18.0 7.32 33 21.4 6.17 23 25.9 5.11 26 26.4 5.0187 29.6 4.48 26 29.9 4.44 20 31.1 4.27 34 31.7 4.19 20 32.4 4.10 77 33.14.02 23 33.5 3.97 64 36.5 3.66 38 39.1 3.42 40 41.9 3.20 32 46.4 2.91 2352.7 2.58 25 Diffractometer: Miniflex Rigaku (Elexience)

The invention also relates to the polymorphic form of the laevorotatoryenantiomer of modafinil described as CRL 40982 form IV, characterised inthat it produces an X-ray diffraction spectrum comprising intensitypeaks at the interplanar spacings: 12.38; 8.58; 7.34; 6.16; 5.00; 4.48;4.09; 3.66 Å, the most characteristic peaks corresponding to theinterplanar spacings of 12.38; 8.58; 7.34; 5.00; 4.09 Å.

More specifically, form IV of (−)-modafinil is characterised in that itproduces the following X-ray diffraction spectrum in which d representsthe interplanar spacing and I/Io the relative intensity comprisingintensity peaks at the interplanar spacings:

CRL 40982 FORM IV 2 Theta (degrees) d (Å) I/Io (%) 6.37 13.88 26 7.1412.38 69 8.60 10.27 23 10.30 8.58 100 12.04 7.34 49 14.37 6.16 24 15.655.66 11 17.30 5.12 29 17.72 5.00 60 19.12 4.64 15 19.81 4.48 25 20.824.26 10 21.24 4.18 12 21.70 4.09 51 23.28 3.82 9 24.30 3.66 30 25.183.53 9 26.02 3.42 21 27.13 3.28 9 27.90 3.20 15 Diffractometer: SiemensAG.

The invention also relates to the polymorphic form of the dextrorotatoryenantiomer of modafinil referred to as CRL 40983 form V, characterisedin that it produces an X-ray diffraction spectrum comprising intensitypeaks at the interplanar spacings 9.63, 5.23; 5.03, 4.74, 4.66, 4.22,4.10, 3.77 (Å).

CRL 40983 FORM V 2 Theta (degrees) d (Å) I/Io (%) 6.65 13.27 22 7.2412.21 5 9.17 9.63 51 10.38 8.51 19 12.28 7.20 15 14.33 6.17 14 15.815.60 4 16.95 5.23 68 17.64 5.03 100 18.69 4.74 51 19.03 4.66 58 20.064.42 3 21.06 4.22 91 21.67 4.10 64 22.39 3.97 17 23.61 3.77 55 24.643.61 8 25.40 3.50 13 26.21 3.40 20 26.95 3.31 18 Diffractometer: BrukerGADDS

The invention also relates to the dimethyl carbonate solvate of(−)-modafinil, characterised by the following diffraction spectrum inwhich d represents the interplanar spacing and I/Io the relativeintensity:

DIMETHYL CARBONATE SOLVATE 2 Theta (degrees) d (Å) I/Io (%) 7.17 12.3138 9.12 9.69 29 9.72 9.09 16 10.35 8.54 35 12.17 7.27 100 14.25 6.21 1616.26 5.45 10 17.36 5.10 13 17.72 5.00 21 18.35 4.83 9 19.16 4.63 919.88 4.46 14 21.04 4.22 12 21.49 4.13 25 21.73 4.09 24 23.49 3.78 2224.55 3.62 35 25.24 3.53 8 26.05 3.42 9 26.88 3.32 7 27.48 3.24 13 27.813.21 10 28.79 3.10 8 Diffractometer: Siemens AG.

The invention also relates to the acetic acid solvate of thelaevorotatory and dextrorotatory enantiomers of modafinil which can beobtained by the recrystallisation process according to the invention,characterised in that it produces a X-ray diffraction spectrumcomprising intensity peaks at the interplanar spacings: 9.45; 7.15;5.13; 4.15; 3.67 (Å).

ACETIC ACID SOLVATE 2 Theta (degrees) d (Å) I/Io (%) 6.64 13.30 8.5 7.1512.35 15 9.36 9.45 100 10.43 8.48 6.5 12.38 7.15 25 14.38 6.16 15 16.375.41 8 17.29 5.13 28 17.82 4.97 21 18.24 4.86 16 18.96 4.68 7 19.24 4.616 20.09 4.42 20 21.40 4.15 75 22.55 3.94 21 23.42 3.80 7 24.25 3.67 4024.92 3.57 12 25.21 3.53 9.5 26.15 3.40 11 26.78 3.33 8 26.99 3.30 628.43 3.14 13 28.79 3.10 14 29.63 3.01 7 30.03 2.97 4 32.33 2.77 9 33.132.70 7 34.29 2.61 3 34.86 2.57 7 35.90 2.50 7 Diffractometre: BrukerGADDS

According to another aspect, the invention also relates to a process forconversion from a first crystalline form of one of the enantiomers ofmodafinil to a second crystalline form which is different from theformer, the said process comprising the stages of:

-   -   i) suspending the crystalline form of the said enantiomer of        modafinil in a solvent;    -   ii) recovering the crystalline form obtained.

By way of solvents which may be suitable for this process mention may bemade in particular of acetonitrile.

In general the initial crystalline form is held in suspension at atemperature lower than the homogenisation temperature for a sufficientlength of time to permit total conversion of the initial form. Thisperiod may vary in particular according to the nature of the solvent,the initial crystalline form and the temperature of the medium.Conventionally the crystalline form is held in suspension for at least24 hours at ambient temperature under atmospheric pressure, mostcommonly for approximately 72 hours.

By way of illustration this process is implemented using (−)-modafinil.

In this context, according to a particular embodiment of the invention,the process uses form I in acetonitrile in stage i), as a result ofwhich an acetonitrile solvate of (−)-modafinil is obtained.

By way of indication form I is held in suspension for several days,preferably for 3 days at ambient temperature, at atmospheric pressure.

The invention also relates to the acetonitrile solute of (−)-modafinilwhich can be obtained through the recrystallisation process according tothe invention. It is characterised by the following diffraction spectrumin which d represents the interplanar spacing and I/Io the relativeintensity:

ACETONITRILE SOLVATE 2 Theta (degrees) d (Å) I/Io (%) 5.46 16.17 46 6.2514.14 95 7.17 12.32 51 8.28 10.66 81 9.02 9.79 68 9.51 9.29 53 10.348.54 53 10.84 8.15 63 11.33 7.80 79 12.47 7.09 53 14.02 6.31 45 15.205.83 35 15.76 5.62 34 16.37 5.41 40 17.37 5.10 51 18.10 4.90 46 19.054.66 44 19.36 4.58 37 19.89 4.46 39 20.48 4.33 59 21.14 4.20 55 22.104.02 100 22.65 3.92 60 23.17 3.835 42 23.89 3.72 33 24.72 3.60 38 24.933.57 37 25.81 3.45 37 26.73 3.33 55 27.52 3.24 30 27.97 3.19 30 28.893.09 31 29.44 3.03 27 Diffractometer: Siemens AG.

Pharmaceutical Compositions comprising Polymorphic Forms II, III, IV andV of (−)-Modafinil and (+)-Modafinil Respectively

The invention also relates to pharmaceutical compositions comprising thepolymorphic forms CRL 40982 form II, CRL 40982 form III, CRL 40982 formIV or CRL 40982 form V of (−)-modafinil and form CRL 40983 form II, CRL40983 form III, CRL 40983 form IV and CRL 40983 form V respectively,possibly in association with a pharmaceutically acceptable vehicle.

These compositions may be administered orally, via the mucosa (forexample, the mucosa of the eye, nose, lungs, stomach, intestines,rectum, vagina or the urinary apparatus) or parenterally (for examplesubcutaneously, intradermally, intramuscularly, intravenously orintraperitoneally).

According to a preferred embodiment the pharmaceutical compositionsaccording to the invention are administered orally in the form oftablets, pills, gelules or immediate release or controlled releasegranules, in the form of powder, capsules, suspension of a liquid or ina gel or emulsion, or as a lyophilisate, or preferably in the form oftablets, capsules, suspension in a liquid or in a gel. The vehicle foradministration may comprise one or more pharmaceutically acceptableexcipients which are likely to ensure stability of the polymorphic forms(for example a suspension of a polymorph in an oil).

The pharmaceutical compositions according to the invention comprise theII, III, IV or V polymorphic forms of (−)-modafinil and (+)-modafinilrespectively, possibly as mixtures of each other and/or with one or morepharmaceutically acceptable excipients.

A solid composition for oral administration is prepared by adding one ormore excipients to the active ingredient, in particular a filler, and,if appropriate a binder, an exfoliating agent, a lubricant, a surfactantand an emulsifier, a solubiliser, a colouring agent, a sugar substituteor a taste modifier, with the mixture being formed for example into theform of a table or capsule.

Examples of fillers include lactose, sucrose, mannitol or sorbitol;preparations based on cellulose, such as for example maize starch, ricestarch, potato starch.

Examples of binders include gelatine, gum tragacanth, methylcellulose,hydroxypropylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP), povidone, copovidone, dextran, dextrin, cyclodextrinand its derivatives such as hydroxypropyl-β-cyclodextrin.

Examples of sugar substitutes include aspartame, saccharin and sodiumcyclamate.

Examples of taste modifying agents include cocoa powder, mint invegetable form, aromatic powder, mint in the form of oil, borneol andpowdered cinnamon.

Examples of surfactants and emulsifiers include in particularpolysorbate 20, 60, 80, sucroester (7-11-15), poloxamer 188, 407, PEF300, 400 and sorbitan stearate.

Examples of solubilising agents include miglyol 810, 812, glycerides andtheir derivatives and propylene glycol.

Examples of exfoliating agents include, for example, polyvinylpyrrolidone, sodium carmellose or alginic acid or a salt of the lattersuch as sodium alginate.

Examples of lubricants include magnesium stearate, stearyl magnesiumfumarate, behenic acid and its derivatives.

The pharmaceutical compositions according to this invention may alsocontain another crystalline form of (−)-modafinil or (+)-modafinilrespectively, in particular form I and/or another active ingredient orinactive ingredient as a mixture with one or more other polymorphicforms of modafinil such as form III, form II, form IV and form V.

For the purposes of this invention the term “pharmaceutically acceptablevehicle” covers solvents, dispersion media, antifungal and antibacterialagents, isotonic agents and absorption-delaying agents. The use of suchmedia and agents for pharmaceutically active substances is well known tothose skilled in the art.

The invention also relates to the use of the forms CRL 40982 form II,CRL 40982 form III, CRL 40982 form IV or CRL 40982 form V of(−)-modafinil and the forms CRL 40983 form II, CRL 40983 form III, CRL40983 form IV or CRL 40983 form V of (+)-modafinil respectively for themanufacture of a medication intended for the prevention and/or treatmentof a condition selected from hypersomnia, in particular idiopathichypersomnia and hypersomnia in patients affected by a cancer treated bymorphine analgesics to relieve pain; sleep apnoeas, excessive somnolenceassociated with a disease, obstructive sleep apnoeas, narcolepsy;somnolence, excessive somnolence, excessive somnolence associated withnarcolepsy; disturbances of the central nervous system such asParkinson's disease; protection of the cerebral tissue againstischaemia, alertness disturbances, in particular alertness disturbancesassociated with Steinert's disease, attention disturbances, for exampleassociated with hyperactivity (ADHD); the condition of fatigue, inparticular that associated with multiple sclerosis and otherdegenerative diseases; depression, the depressive condition associatedwith low exposure to sunlight, schizophrenia, rotating shift working,time shifts; eating disturbances, in which modafinil acts as an appetitestimulant, the stimulation of cognitive functions in low doses.

Process for the Preparation Optically Active Modafinil

In accordance with another aspect the invention relates to a process forpreparation of the optical enantiomers of modafinil from (±) modafinilacid, the said process comprising the following stages:

-   -   i) separating the two optical enantiomers of (±) modafinil acid        and recovering at least one of the enantiomers,    -   ii) placing one of the two enantiomers obtained in contact with        a lower alkyl haloformate and an alcohol in the presence of a        base,    -   iii) recovering the product obtained,    -   iv) converting the ester obtained in stage iii) into an amide,    -   v) recovering the product obtained in stage iv).

Preferably the lower alkyl haloformate is a lower alkyl chloroformateand, better still, it comprises methyl chloroformate.

Advantageously the lower alkyl haloformates, among which in particularmethyl chloroformate, used in this process to bring about theesterification of modafinil acid are less toxic than the dimethylsulphate described in the process in the prior art U.S. Pat. No.4,927,855, giving equivalent or better yields. The process is thereforeeasier to use and more suitable for industrial application.

Preferably the operation is conducted in the presence of an equimolarquantity of lower alkyl haloformate and base in stage ii) in relation tooptically active modafinil acid.

It is particularly preferred to use organic bases, more preferablynitrogen-containing bases.

As a particularly preferred base mention may be made in particular oftriethylamine, diisopropylamine, diethylmethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

Preferably the solvent used in stage ii) is a lower aliphatic alcoholsuch as methanol, ethanol or propanol, methanol being particularlypreferred.

According to a particular embodiment the ester obtained from stage ii)is crystallised by the addition of iced water.

Conversion of the ester to amide in stage iv) preferably consists ofammonolysis, i.e. treatment with ammonia.

In this context it is generally preferably to work with an excess ofammonia.

According to a particularly advantageous variant of the invention,ammonia is used in the form of gas.

In a preferred embodiment the ammonolysis reaction is performed in apolar solvent, preferably a protic solvent such as lower aliphaticalcohols, for example in methanol or ethanol, methanol beingparticularly preferred.

The (+) or (−)modafinil acid ester in stage iii) and the (+) or(−)modafinil respectively in stage iv) are recovered using conventionalmethods known to those skilled in the art.

According to another aspect the invention relates to a process for thepreparation of optical enantiomers of modafinil comprising the followingstages:

-   -   a. resolving the two optical enantiomers of (±) modafinil acid        or salts of the same according to a preferential crystallisation        process,    -   b. converting the said isolated enantiomers into an amide,    -   c. recovering the modafinil enantiomer obtained.

According to a preferred embodiment stage b) is performed in two stages:

-   -   b1) converting the said enantiomers into a lower alkyl ester,    -   b2) converting the product obtained in stage b1) into an amide.

According to a particularly preferred embodiment stage b1) is carriedout in the presence of a lower alkyl haloformate, an alcohol and a base,under the conditions described previously.

According to a particularly advantageous embodiment, when b1) isperformed in the presence of methyl chloroformate, a base and an alcoholand c1) comprises an ammonolysis such as described previously, thisprocess in which the (±)-modafinil acid is separated by preferentialcrystallisation gives rise to an overall yield generally of the order of25%. Thus the yield of the (−)-modafinil enantiomer in particularobtained by this process is markedly greater than that obtained in U.S.Pat. No. 4,927,855.

The preferential crystallisation technique is a technique which iswidely used in laboratories and in industry.

This method is based on the alternate crystallisation of two chiralcompounds referred to as R and S, forming a conglomerate in solvent Aand over a given temperature range D_(T). This means that within thistemperature range any mixture of the two antipodes in thermodynamicequilibrium with the solution comprises two types of crystals each ofwhich only contain molecules having the same configuration, which may ormay not incorporate solvent molecules (solvates). The existence of sucha conglomerate, without miscibility in the solid state, is implicitlyaccepted in what follows, at least during the temperature range D_(T)and in the case of solvent A.

Two kinds of factors influence crystallisation of the optical antipodes,on the one hand parameters associated with ternary heterogeneousequilibria and on the other hand factors affecting the kinetics ofcrystallisation.

The parameters associated with ternary heterogeneous equilibriacomprise:

-   -   the positions of the crystallisation surfaces for the solid        species which are deposited at each temperature and more        particularly the solubilities of the stable and metastable        phases, of the s(+) racemic mixture and the antipodes s(+)=s(−)        in relation to temperature, and the ratio of solubilities        α=s(±)/s(+),    -   the extent of the stable and metastable domains for the solid        solutions, the racemate, the racemic solvate, the active        solvates and the polymorphic varieties of the crystallised        solids.

The factors acting on the kinetics of crystallisation include

-   -   factors internal to the crystals, associated with the bonds        between molecules, which cannot be modified by the experimenter,    -   external factors which can be modified by the experimenter;        these are the nature of the solvent, the nature and        concentration of impurities, the supersaturation acquired in        relation to time, the temperature range D_(T), the speed and        manner of stirring, the mass and particle size of the nuclei,        the wall effect, etc.

These two kinds of factors directly influence the yield, the purity ofthe phases obtained and the conduct of the separation operations. Thefeasibility of filtration also depends on the particle size spectrum andthe habits of the crystals, the viscosity of the suspension, the vapourpressure of the solvent, the supersaturation of each of the antipodesand the possible presence of a true racemate of a metastable nature.These choices may also affect the kinetics of racemisation of theantipodes or degradation of the molecule.

For each combination comprising the pair of antipodes (R and S) and thesolvent (A), the factors affecting the kinetics are of a particulartype.

Two preferred methods of crystallisation are mainly distinguished:

-   -   conventional processes, described as SIPC, for “Seeded        Isothermal Preferential Crystallization” and their polythermic        variants, and    -   the process referred to as AS3PC, for “Auto-Seeded Polythermic        Programmed Preferential Crystallization”.

In the AS3PC preferential crystallisation method which is referred to asbeing auto-seeded, the system is placed under conditions such that ititself generates its own seeds to produce the required enantiomer, whilein the SIPC method these seeds are introduced by seeding. The two typesof processes are described in greater detail below.

For more information concerning resolution processes by preferentialcrystallisation by the AS3PC methods reference may be made in particularto the documents by G. Coquerel, M.-N. Petit and R. Bouaziz, Patent EP0720595 B1, 1996, E. Ndzié, P. Cardinaël, A.-R. Schoofs and G. Coquerel,Tetrahedron Asymmetry, 1997, 8(17), 2913-2920, L. Courvoisier, E. Ndzie,M.-N. Petit, U. Hedtmann, U. Sprengard and G. Coquerel, ChemistryLetters, 2001, 4, 364-365.

According to a particular embodiment, the process for resolution of theoptical enantiomers of (±) modafinil acid or its salts is a seeded SIPCor S3PC process, the said process comprising the following stages:

-   -   a) homogenisation of an combination comprising a racemic mixture        of crystals in the form of a conglomerate of the first        enantiomer of modafinil acid at a temperature T_(D), for which        the defining point E, defined by the variables concentration and        temperature T_(D), lies within the monophase domain of the        dilute solution,    -   b) rapidly cooling the solution prepared in stage a) initially        at the temperature T_(D) down to the temperature T_(F),    -   c) seeding the solution obtained in stage b) while cooling (i.e.        between T_(L) and T_(F)) or when cooling is complete (i.e. at        T_(F)) with very pure seeds of the first enantiomer,    -   d) harvesting crystals of the first enantiomer,    -   e) adding the racemic mixture of crystals in the form of        conglomerate to the mother liquors resulting from the harvest        performed in stage d) and homogenising the new combination by        heating to a temperature T_(D), so that the defining point E′ is        symmetrical for E with respect to the plane of the racemic        mixture of the solvent, antipode (−), antipode (+) system, the        said point E′ lying within the monophase domain of the dilute        solution,    -   f) rapidly cooling the solution obtained in stage e), initially        at temperature T_(D), down to temperature T_(F),    -   g) seeding the solution obtained in stage f) with very pure        seeds of the second enantiomer,    -   h) harvesting the crystals of the second enantiomer,    -   i) adding the racemic mixture in the form of a conglomerate of        crystals resulting from the crystal harvest made in stage h) to        the mother liquors and homogenising the new combination by        heating to a temperature T_(D) in order to obtain a composition        identical to that of the combination having the initial defining        point E,    -   j) repeating stages a), b), c), d), e), f), h) and j) to        subsequently obtain the first and then the second of the two        enantiomers.

Reference is frequently made to these two methods by describing them as“SIPC” and “S3PC” respectively, the latter being a variant of SIPC asdescribed in detail further on in the description.

In what follows, for the purposes of this invention,

-   -   T_(F) represents the temperature at the end of crystallisation        and filtration, located in the three-phase domain,    -   T_(L) represents the homogenisation temperature of the racemic        mixture,    -   T_(D) represents the starting temperature at which the starting        mixture is a homogenous solution,    -   antipode means an enantiomer.

Preferably the process for the resolution of these two opticalenantiomers of (±)-modafinil acid or salts of these by preferentialcrystallisation is an AS3PC self-seeded process, the said processcomprising the following stages:

-   -   a) creating a combination comprising a racemic mixture of the        crystals in the form of a conglomerate of the first enantiomer        of modafinil acid and solvent, for which the defining point E,        defined by the variables concentration and temperature T_(B),        lie within the two-phase domain of the enantiomer in excess, and        is in equilibrium with the saturated solution,    -   b) applying a temperature cooling programming function to the        two-phase mixture prepared in stage a), this programming        function being such that the mother liquors remain slightly        supersaturated, encouraging growth of the enantiomer present in        the form of crystals while preventing spontaneous nucleation of        the second enantiomer present in the solution,    -   c) throughout the time of crystal growth in stage b) adopting a        rate of stirring which increases slightly in relation to time so        that it is at all times sufficiently slow to encourage growth of        the first enantiomer while avoiding the generation of        excessively large shear forces bringing about uncontrolled        nucleation but sufficiently fast to achieve a homogeneous        suspension and rapid renewal of the mother liquor around each        crystallite of the first enantiomer,    -   d) harvesting the crystals of the first enantiomer,    -   e) adding the racemic mixture of crystals in the form of a        conglomerate to the mother liquors resulting from the harvest        performed in stage d) and bringing the new combination to a        temperature threshold T_(B) during the time necessary to achieve        thermodynamic equilibrium so that the defining point E′ is        symmetrical for E with respect to the plane of the racemic        mixtures for the solvent, antipode (−), antipode (+) system, the        said point E′ lying within the two-phase domain of the second        enantiomer which is in excess and in equilibrium with its        saturated solution,    -   f) applying the same cooling programming function as in stage b)        to the two-phase mixture prepared in stage e) containing the        second enantiomer so that the mother liquors remain slightly        supersaturated during crystallisation in order to encourage        growth of the enantiomer present in the form of crystals while        preventing spontaneous nucleation of the first enantiomer        present in the solution,    -   g) adopting a stirring speed which increases slightly in        relation to time over the entire time of crystal growth in        stage f) so that it is at all times sufficiently slow to        encourage growth of the second enantiomer while avoiding        generation of excessively large shear forces giving rise to        uncontrolled nucleation, but sufficiently fast to obtain a        homogeneous suspension and rapid renewal of the mother liquor        around each crystallite of the second enantiomer,    -   h) harvesting crystals of the second enantiomer,    -   i) adding the racemic mixture of crystals in the form of        conglomerate to the mother liquors resulting from the crystal        harvest performed in stage g) in order to obtain a combination        in which the composition is identical to that of the initial        combination E,    -   j) repeating stages a), b), c), d), e), f) g), h) and i) to        obtain the first and then the second of the two enantiomers        successively.

In what follows, for the purposes of this invention, T_(HOMO) shall meanthe homogenisation temperature of the combination comprising the racemicmixture, the first enantiomer and the solvent.

Thus in stage (a) of the process according to the invention the choiceof the solvent or solvents and the working temperature range are definedin such a way so as to obtain simultaneously:

-   -   antipodes which form a conglomerate and of which any racemate is        metastable in the working temperature range,    -   liquors which are sufficiently concentrated but of low viscosity        and low vapour pressure,    -   the absence of solvolysis and racemisation,    -   stability of the solvates if these are present at equilibrium        and they are resolvable enantiomers.

In stages (a) and (e) of the process according to the invention, thetemperature T_(B) is higher than the temperature T_(L) forhomogenisation of the quantity of racemic mixture present in the initialsuspension, in that from the curve for the change in T_(HOMO) inrelation to the excess of enantiomer and for a constant concentration ofthe racemic mixture X_(L) the said temperature T_(B) is defined in sucha way that the mass of fine crystals of the first enantiomer from stages(a) and (i) and the second enantiomer from stage (e), in equilibriumwith their saturated solutions, represent at most 50% and preferablybetween 25% and 40% of the expected harvest.

In stages (b) and (f) of the process according to the invention, thefunction for programming cooling from temperature T_(B) to T_(F),appropriate to the experimental assembly, is defined so as to:

-   -   achieve slight supersaturation throughout the time for        crystallisation of the enantiomer present in the form of        crystals at the start of each cycle, this slight supersaturation        giving rise to gentle growth and secondary nucleation,    -   achieve maximum supersaturation of the other enantiomer at T_(F)        without primary nucleation,    -   obtain a harvest of crystals in stages (d) and (h) which after        addition of the racemic mixture and the provision of make-up in        stages (e) and (i), makes it possible to perform the operations        cyclically.

In fact every experimental assembly has an influence on thesupersaturation capacities of the mixtures used and the efficiency ofstirring, and as a consequence the function programming cooling must beadapted to the circumstances in which the process is carried out.However the temperature T_(B), the solubilities of the racemic mixturein relation to temperature, and the T_(HOMO) curve in relation to theexcess of enantiomer for a constant concentration of the racemic mixtureX_(L) are themselves wholly independent of the experimental assembly.

The cooling programming function, which is the function linkingtemperature with time, is determined in its part from T_(L) to T_(F) bycooling of the solution of concentration X_(L) from T_(L)+1° C. toT_(F), where T_(F) is lower than T_(L)−(T_(HOMO)−T_(L)), in order toobtain a stable saturated solution without primary nucleation whilepermitting a double harvest of the initial enantiomer excess and thesaid cooling programming function is determined in its part from T_(B)to T_(L) by extrapolation of the same function as established fromT_(L)+1° C. to T_(F).

The process for the preferential crystallisation of (±)-modafinil acidor salts of the same has other advantageous features alone or incombination such that:

-   -   in stages (a) and (i) the mass of fine crystals of the first        enantiomer in equilibrium with the saturated solution represents        between approximately 25% and 40% of the expected harvest, 50%        representing a maximum limit,    -   in stage e) the mass of fine crystals of the second enantiomer        in equilibrium with its saturated solution represents between        approximately 25% and 40% of the expected harvest, 50%        representing a maximum limit,    -   in stages (b) and (f) the heat released accompanying deposition        of the first enantiomer and the second enantiomer is        incorporated into the temperature programming function,    -   in stages (e) and (i) compensatory additions of solvent are        made,    -   in stages (a), (e) and (i) the fine crystals of the racemic        mixture in the form of conglomerate added were subjected to        prior treatment to accelerate the dissolution stage, such as        grinding and sieving, treatment with ultrasound waves or partial        lyophilisation, before being added; these treatments being also        for the purpose of providing fine crystals capable of generating        a large surface area for crystal growth,    -   in stages (a), (e) and (i) involving dissolution, the rate of        stirring is high in comparison with stages (c) and (g).

In addition to the heterogeneous equilibrium data required forimplementing the AS3PC process, the operations are also subject toadjustable kinetic constraints, particularly the cooling function, andthese are specific to each solvent/enantiomer combination.

According to one embodiment the solvent used in stage a) of the SIPC,S3PC or AS3PC processes is absolute or denatured ethanol, possibly in amixture with an organic or mineral base, or with one or more solventscapable of improving the solubility of the racemic mixture in ethanol.

As a variant, the solvent used in stage a) of the SIPC, S3PC or AS3PCprocesses is 2-methoxyethanol or methanol, possibly mixed with anorganic or mineral base, and/or one or more solvents capable ofimproving the solubility of the racemic mixture in ethanol.

According to a particularly advantageous embodiment the solvent used instage a) of the SIPC or AS3PC process is ethanol, 2-methoxyethanol ormethanol. For (±)-modafinil acid the filtration temperature T_(F)preferably lies between 0° C. and 40° C.

In the case of ethanol the temperature T_(F) preferably lies between 0°C. and 25° C., and better still it is close to 18° C. or 17° C.

In the case of 2-methoxyethanol or methanol, the temperature T_(F)preferably lies between 20° C. and 35° C. and in particular is close to30° C.

Preferably the concentration of the racemic mixture in stage a) thenlies between 2 and 50% by mass, more preferably between 2 and 30% bymass, and, better still, close to 5.96% by mass in the case of ethanol,15.99% in the case of 2-methoxyethanol and 25.70% in the case ofmethanol.

In this context it is most particularly preferred that the enantiomerexcess in stage a) should be between 1 and 50% by mass, more preferablybetween 1 and 20% by mass, and, better still, close to 11% by mass inthe case of ethanol, 8% by mass in the case of 2-methoxyethanol and 10%by mass in the case of methanol.

In the SIPC and S3PC processes the temperature T_(D), the temperature atwhich the starting mixture is a homogeneous solution, depends onconcentration and then generally lies between 35° and 50° C. when thesolvent is under reflux. The cooling from temperature T_(D) to T_(F) isvery fast so as to remain within the monophase domain and is preferablycarried out in less than 20 min, for example by quenching.

According to a preferred embodiment of the AS3PC process the temperatureT_(B) then lies between the temperatures T_(L) and T_(HOMO). Thetemperature T_(B) may in particular lie between 25° C. and 50° C.

By way of example, in the case of ethanol, when the enantiomer excess isclose to 11% by mass temperature T_(B) preferably lies between 25° C.and 40° C., in particular between 30.1° C. and 36.2° C. and morepreferably close to 33.5° C. or 31.5° C.

In the case of 2-methoxyethanol, when the enantiomer excess is close to8% by mass temperature T_(B) preferably lies between 35° C. and 50° C.,in particular between 39.1° C. and 47.9° C. and more preferably close to41° C.

In the case of methanol, when the enantiomer excess is close to 10% bymass, temperature T_(B) preferably lies between 40° C. and 55° C., inparticular between 45.1° C. and 53.9° C. and more preferably close to46.5° C.

It is most particularly preferred that cooling from T_(B) to T_(F) instage b) be carried out in a time which is sufficiently long for theaverage mass of desired enantiomer crystals harvested to be large, butsufficiently short to prevent the other enantiomer from crystallising,thus obtaining a high optical purity, in particular greater than 85%.Cooling is generally monitored by polarimetry to determine the rightmoment for filtration. Preferably cooling takes place between 50 and 70minutes, better still, it takes 60 minutes when the solvent used isethanol.

Likewise, the length of the plateau at temperature T_(F) for the SIPC,AS3PC and S3PC processes is preferably sufficiently great to allow alarge mass of the desired enantiomer crystals to be harvested, but nottoo long so as to prevent the other enantiomer from crystallising at thesame time as the desired enantiomer, thus obtaining a high opticalpurity.

According to a preferred embodiment the length of the temperatureplateau T_(F) lies between 15 and 60 minutes, preferably about 60minutes.

A person skilled in the art will be able to adjust the rate of stirringto the type of reactor used in SIPC, S3PC or AS3PC processes. By way ofindication, for a 2 or 10 litre reactor the speed at which the medium isstirred may be held between 150 and 250 rpm.

In a particularly useful manner these methods of preferentialcrystallisation make it possible to isolate the optical enantiomers ofmodafinil, in particular the laevorotatory enantiomer, in yields whichare very much greater than those obtained by resolution using a chiralagent. The yields obtained are generally of the order of 90%, or evenhigher, in relation to the (+) or (−) optical enantiomer, or of theorder of 45% or more in relation to the racemic mixture.

AS3PC, SIPC and S3PC Methods

The AS3PC and SIPC methods mentioned above are described below.

Ternary Heterogeneous Equilibria: R and S Antipodes, and Solvent A

For example the work by J. E. Ricci (Ed. Dover Publication Inc. NewYork, 1966, The Phase Rule and Heterogeneous Equilibrium) deals with thegeneral case of heterogeneous equilibria in ternary systems. Thedescription below will be restricted to particular aspects of theternary system, A (achiral solvent), R and S (enantiomers which cannotbe racemised in the temperature domain used), which are necessary for anunderstanding of the various processes of preferential crystallisation.

In order to show the special role of the solvent this ternary systemwill be represented by a right prism having a cross-section which is aright-angled isosceles triangle on which the temperature is plotted onan axis perpendicular to the plane of concentration.

The fact that the thermodynamic variables for the two enantiomers, Tf,ΔHf, solubility in a achiral solvent, etc., are identical has the resultthat representation of the domains is symmetrical with respect to thevertical plane A-TS-T, which includes the optically inactive mixtures,in FIG. 1. The following simplifications have been made in order toassist an initial description of this system:

-   -   the only phases which crystallise out are the pure constituents        in a given arrangement (absence of racemate, solvate and        polymorphism in the case of the antipodes),    -   miscibility between the independent constituents is zero in the        solid state,    -   the solvent has a melting point which is appreciably lower than        that of the antipodes,    -   in the temperature range used the solubility of an antipode is        not influenced by the presence of the other in the solution        (Meyerhoffer's law is respected), which is reflected in the        ratio having the value α=2).

Representation of Ternary Equilibria as a Function of Temperature

FIG. 1 shows the domains for the following phases:

-   -   the monophase domain for the dilute solution (φ=1),    -   the two crystallisation surfaces for the constituents bounding        the two-phase domains (φ=2).    -   the surface for deposition of the solvent is confined to the        vicinity of A because the melting point of this constituent is        appreciably lower than that of the other constituents, in        accordance with the conditions mentioned above.    -   the three monovariant curves (φ=3) or eutectic valleys        originating from binary eutectic points,    -   the ternary eutectic invariant at Tε (φ=4), above which the        three constituents are crystallised.

FIG. 2 shows in a superimposed fashion the two isothermal cross-sectionsof the ternary displayed in FIG. 1 at T_(D) and T_(F). At eachtemperature the cross-section consists of four domains as detailed inthe table below.

Number of Domain Nature of the phases in phases in Temperature boundaryequilibrium equilibrium T_(D) A-S_(D)-I_(D)-S′_(D) dilute solution 1T_(D) R-S_(D)-I_(D) solution + crystals of R 2 T_(D) S-S′_(D)-I_(D)solution + crystals of S 2 T_(D) I_(D)-R-S solution + crystals of R andS 3 T_(F) A-S_(F)-I_(F)-S′_(F) dilute solution 1 T_(F) R-S_(F)-I_(F)solution + crystals of R 2 T_(F) S-S′_(F)-I_(F) solution + crystals of S2 T_(F) I_(F)-R-S solution + crystals of R and S 3

Isopleth Cross-Section RYT

FIG. 3 shows the isopleth cross-section R-Y-T which is fundamental to anunderstanding of crystallisation by the cooling of ternary solutions inthermodynamic quasi-equilibrium. This cross-section is also necessaryfor following non-equilibrium processes, SIPC, variants and AS3PC. Thisplane is the geometric locus of the points fulfilling the relationship:

X_(A)/X_(S)=(1−Y)/Y=constant, with X_(A) and X_(S) providing thefractions by mass of solvent and antipodes S.

In FIG. 3 it is possible to see

-   -   the monophase domain of the ternary solution,    -   the liquidus for antipode R, this curve representing the        intersection of plane R-Y in FIG. 2 with the crystallisation        surface for that constituent. This stable equilibrium curve        originates at the melting point of antipode R (not shown) and is        bounded on the low temperature side by point L which forms part        of the ternary eutectic valley for the racemic mixtures. This        latter curve and the line of the conoid at T_(L) (horizontal        segment at T_(L)) are the boundary of the two-phase        domain—saturated solution plus crystals of R. It extends into        the underlying three-phase domain through a solubility curve for        the same antipode R which is of a metastable nature (dashed        lines),    -   the three-phase domain: crystals of T and S, plus saturated        solution. This domain is bounded at the top by the horizontal        line of the conoid for R, and at the bottom by the line of the        invariant ternary eutectic plane and on the left by the line Lm        of one of the conoids relating to the antipode S.    -   the line KL of the crystallisation surface for antipode S which        bounds the two-phase domain at the top—saturated solution plus        crystals of S. This domain is bounded in its lower part by the        lines of the two conoids for S: gm and Lm. The location of the        second line Lm of the conoid for S in relation to the metastable        solubility curve for R, which is an extension of EL, will be        discussed below in relation to the relative position of F1 and F        in relation to the ratio of solubilities α,    -   The ternary invariant at the temperature Tε above which the        three crystallised constituents A, R and S lie.        Change on Cooling and with Thermodynamic Quasi-Equilibrium of        the Ternary Solutions having a Slight Excess of Enantiomer

It is taken in what follows that the overall point for the system (i.e.the point representing the overall composition of the mixture) lies onthe vertical passing through point E in FIGS. 2 and 3, and its preciseposition is defined by its temperature (or level). Only the followingtemperature range is considered:

-   -   T_(D): temperature at which the starting mixture is a        homogeneous solution, and    -   T_(F): temperature at the end of crystallisation and filtration,        which lies in the three phase domain.

This overall composition E corresponds to a racemic solution which isslightly enriched by a mass M of the antipode R forming a total mass Mt(the enantiomer excess R−S/R+S generally lies between 4% and 9%).Equilibrium conditions are obtained by very slow cooling and by seedingin the solid phase(s) when the overall point E defining the mixturereaches a domain where this (these) phase(s) is (are) present atequilibrium.

At the starting temperature T_(D) the solution is homogeneous. Thefollowing are observed in succession on cooling:

-   -   crystallisation of the antipode R alone, from T_(HOMO) to T_(L),        at the same time the solution point moves on the solubility        curve for antipode R, that is from point E at level T_(HOMO) to        point L within the isopleth cross-section R-Y. At point L, mass        M of crystals R in equilibrium with saturated solution is given        by Mt (X_(E)−X_(L)/1−X_(L))=M and corresponds to the enantiomer        excess present in the initial solution (FIG. 3), the abscissas        of the points L, E and R correspond to the compositions, and 1        (FIG. 3).    -   from T_(L) the solution point moves from L to I_(F) along the        line of fixed gradient containing the solutions of racemic        composition shown in FIG. 2, thus leaving the isopleth        cross-section R-Y in FIG. 3, crystals of R and S are then        deposited simultaneously and in equal quantities. Resolution        cannot be effected under equilibrium conditions at temperatures        below T_(L).        Change in the Solution when Resolving by Conventional Control in        Accordance with the SIPC Process

Crystallisation of the First Antipode in Excess

The previous solution E is homogenised at temperature T_(D) (FIGS. 4 and5). In order to make it supersaturated it is cooled rapidly totemperature T_(F) without any crystallisation occurring. This solution,which is not in thermodynamic equilibrium, is then seeded with very pureseeds of the antipode R having the same chirality as the antipode inexcess. The isothermal crystallisation of antipode R is established andthe point representing the solution moves within the cross-section R-Y-Tfrom E to the level T_(F) with which it is first coterminous to F wherefiltration is rapidly performed. The mass of antipode R recovered is 2 Mor again is equal to Mt (X_(E)−X_(F)/1−X_(F)).

Crystallisation of the Second Antipode, Cyclicity of the Operations

The above fundamental operation thus gave rise to a solution F enrichedwith antipode S. By adding a mass 2 M of racemic mixture (equal to thatof the antipode recovered) and heating this mixture to temperature T_(D)a homogeneous solution E′ which is symmetrical for E with respect to thevertical plane A-(RS)-T is obtained. The process making it possible toobtain a mass 2 M of antipode S will itself also be represented bysymmetrical movement of the above in relation to this median plane. Thefollowing operations are then performed in sequence:

-   -   solution E′ which is homogeneous at temperature T_(D) is first        cooled to T_(F), then,    -   seeded with very pure seeds of antipode S, the growth of this        antipode displaces the point representing the solution on the        horizontal segment E′F′ (at the level T_(F)),    -   when the solution point is the same as F′, the solution is        filtered and provides a mass 2 M of antipode S,    -   after a further addition of a mass 2 M of racemic mixture and a        further heating to T_(D) a homogeneous solution is again        obtained and its representative point is the same as the initial        point E at level T_(D),

the rest of the process is merely a repeat of this cycle of operations.

Variants in the SIPC Process

The literature (Amiard, G., 1956, Bull. Soc. Chim. Fr. 447, Collet, A.,Brienne, M. J., Jacques, J., 1980, Chemical reviews 80, 3, 215-30,Noguchi Institute, 1968, patent GB 1 197 809) is based on the abovegeneral scheme; the main modifications which have appeared in theliterature are classified as follows:

a) Spontaneous Primary Nucleation of the Antipode in Excess

-   -   When (±)-threonine is separated (Amiard, G., 1956, Bull. Soc.        Chim. Fr. 447), the primary nucleation of the antipode in excess        occurs spontaneously within the supersaturated homogeneous        solution. This primary nucleation occurs when point E        representing the composition of the whole lies within the        three-phase domain and the solution is not stirred (Collet, A.,        Brienne, M. J., Jacques, J., 1980, Chemical Reviews 80, 3,        215-30).

b) Seeding During Cooling (S3PC)

-   -   This protocol is the one most frequently found in the literature        (Noguchi Institute, 1968, patent GB 1 197 809) when the process        differs from SIPC. There are differences between the procedures        cited, but nevertheless the following common broad lines can be        identified:        -   cooling of the homogeneous solution from T_(D) to a            temperature below to T_(L) but above T_(F),        -   seeding of the supersaturated homogeneous solution located            in the three-phase domain with seeds of the same chirality            as the antipode in excess,        -   cooling to T_(F). In some cases the latter stage is            controlled by precise temperature programming (Noguchi            Institute, 1968, patent GB 1 197 809).

These protocols will be grouped together under the same term “S3PC” for“Seeded polythermic programmed preferential crystallization” althoughtemperature programming is not present or is limited to the second stageof cooling.

Change in the Solution Point in the Case of Resolution by ProgrammedControl and Self-Seeding in Accordance with the AS3PC Process Accordingto the Invention

In order to achieve a better comparison between conventional processesand the AS3PC process the initial point E is chosen arbitrarily in FIGS.6 and 7 to be the same as in the previous case; however, as will beapparent in the examples which follow, the AS3PC process makes itpossible to take a point E which is further away from the plane A-(RS)-Tand therefore with a larger enantiomer excess and thus improve theharvest of crystals in each operation.

Crystallisation of the First Antipode in Excess

At the start of the process, and contrary to conventional protocols, thewhole, crystals plus solution, is no longer homogeneous but is raised tothe temperature T_(B). The initial solution is then in equilibrium withthe crystals of the enantiomers in excess (for example R in FIG. 7). Thepoints representing the solution (S_(E)) and the whole (E) are thereforenot the same from the start of the process. The two-phase mixture issubjected to a programmed temperature reduction function without theaddition of seed crystals. The point representing the solution describesa curve S_(E)F, contained within the plane R-Y-T, which depends on thekinetics of cooling (FIG. 7). With correctly adjusted kinetics, growthof the enantiomer crystals in excess occurs at the start,crystallisation then progressing towards a simultaneous regimen ofgrowth plus secondary nucleation. When the point representing thesolution reaches the point F, filtration is performed to recover a mass2 M of crystals of antipode R.

Crystallisation of the Second Antipode, Cyclic Nature of the Operations

From point F, which corresponds to the above parent solution, there is amove to point E, which is symmetrical for E with respect to the verticalplane A-(RS)-T, by adding a mass 2 M of the racemic mixture and heatingto temperature T_(B). The enantiomer excess is then profited from totake up a position in the two-phase domain containing the saturatedsolution and the crystals of the antipode in excess. To begin with theracemic mixture added during the passage from F to E (as from F′ to E)will be ground and sieved so as to accelerate the stage of dissolutionof the two antipodes and more particularly the antipode of which thereis less, and thus permit the formation of a large number of crystals ofthe antipode in excess which has the role of the seeds added inconventional processes.

The saturated solution S′_(E), which is symmetrical for S_(E) withrespect to the plane A-(RS)-T is subjected to the same cooling function.The crystals present from the start of cooling grow and then take partin a double mechanism of growth+secondary nucleation. As in the case ofthe first crystallisation no seeding is therefore necessary.

During this time the point representing the solution moves along a curveS_(E′)F′ contained within the plane of the isopleth cross-section S-Y′-Twhich is symmetrical with respect to the bisecting plane A-(RS)-T.

When the solution reaches the representative point located at F′,filtration is performed to harvest a mass 2 M of ground and sievedracemic mixture followed by raising the temperature to T_(B) yieldingthe two-phase mixture at the starting equilibrium.

Continuation of the process consists of repeating this cycle ofoperations yielding crystals of antipode R and S alternately.

Necessary Conditions for Implementing the AS3PC Process

-   -   a) The equimolar mixture of optical antipodes produces a        conglomerate (pure antipodes or solvates) in the solvent used        within the temperature range T_(B)-T_(F); however the existence        of a metastable racemate is not a handicap.    -   b) The molecules which are to be resolved are stable in this        solvent and in the temperature range used between T_(B) and        T_(F).    -   c) It is necessary to determine the ternary equilibrium        temperatures T_(L) and T_(HOMO). Temperature T_(L) is the        temperature at which the racemic mixture dissolves in the        absence of any enantiomer excess in the solution. Once T_(L) has        been determined, the temperature T_(HOMO) corresponds to the        homogenisation temperature of the solution. It depends on the        starting enantiomer excess and the ratio α of the solubilities        of the racemic mixture and the antipode at T_(L). Knowledge of        the supersaturation capacities of the solutions between T_(L)        and T_(F) is also necessary, depending upon the cooling kinetic,        the form of stirring, the nature of the vessel and the particle        size of the crystals of the antipode in excess. To a first        approximation, the time to the appearance of crystals by primary        nucleation in the homogeneous racemic solution L cooled from a        temperature slightly above T_(L) using the same kinetics yields        an indication of the supersaturation capacity tolerated by the        conglomerate under these experimental conditions. This method of        operation has been taken into account in the examples.    -   d) Knowledge of the kinetics of dissolution of a known mass of        racemic mixture (of a given particle size) dispersed in the        solution at temperature T_(B). A few tests will be sufficient to        discover this time.

In what follows the examples and figures are provided by way of anon-restrictive illustration of this invention.

FIGURES

FIG. 1 is a perspective view of the ternary system solvent A—antipodeR—antipode S, in relation to temperature and crystallisation surfacesfor each constituent and compositions of the doubly saturated solutions(monovariant curves); this figure also shows the isotherms attemperatures T_(D) and T_(F) and the ternary eutectic plane at thetemperature Tε including four phases.

FIG. 2 is a projection onto the plane of concentrations of theequilibria at T_(D) and T_(F), as well as a representation of the lineof the isopleth cross-section RY on which point E represents thecomposition of the initial mixture slightly enriched in antipode R whichwill deposit this same antipode.

FIG. 3 is the isopleth vertical cross-section RY in FIG. 2 containingthe composition points for the antipode in excess and that of theinitial solution E on which the path of the solution point for a mixtureof composition X_(E) at equilibrium and on cooling is shown (as a boldline). For T<T_(L) the solution point no longer falls within thiscross-section.

FIG. 4 is a projection onto the concentrations plane of the path of thesolution point (as a bold line) during alternating resolution byisothermal control at temperature T_(F) and seeded in accordance withthe SIPC method.

FIG. 5 is the vertical isopleth cross-section containing the straightline RY in FIG. 4 and illustrating the path of the solution point (as abold line) from E to F during isothermal control (to T_(F)) and seededaccording to the SIPC method.

FIG. 6 is a projection onto the concentrations plane of the path of thesolution point (as a bold line) when resolving by the self-seededprogrammed polythermal process (AS3PC).

FIG. 7 is the vertical isopleth cross-section containing the straightline RY in FIG. 6 and illustrating the path of the solution point (as abold line) from S_(E) to F during resolution by the self-seededprogrammed polythermal process according to the invention (AS3PC).

FIG. 8 is a projection on the concentrations plane of the path of thesolution point (as a bold line) during resolution by the self-seededprogrammed polythermal process (AS3PC) and confirming the relationships(±)<2−α.

All the isothermal cross-sections and isopleths illustrated in thesefigures have composition variables expressed as fractions by mass.

FIG. 9 shows the powder X-ray diffraction spectrum obtainedcorresponding to form II of the laevorotatory enantiomer anddextrorotatory enantiomer of modafinil respectively (Diffractometer:Miniflex Rigaku (Elexience).

FIG. 10 shows the powder X-ray diffraction spectrum obtainedcorresponding to form III of the laevorotatory enantiomer anddextrorotatory enantiomer of modafinil respectively (Diffractometer:Miniflex Rigaku (Elexience).

FIG. 11 shows the powder X-ray diffraction spectrum obtainedcorresponding to form IV of the laevorotatory enantiomer anddextrorotatory enantiomer of modafinil respectively (Diffractometer:Siemens AG).

FIG. 12 shows the powder X-ray diffraction spectrum obtainedcorresponding to the dimethyl carbonate solvate of the laevorotatoryenantiomer and the dextrorotatory enantiomer of modafinil respectively(Diffractometer: Siemens AG).

FIG. 13 shows the powder X-ray diffraction spectrum obtainedcorresponding to the acetonitrile solvate of the laevorotatoryenantiomer and dextrorotatory enantiomer of modafinil respectively(Diffractometer: Siemens AG).

FIG. 14 shows the powder X-ray diffraction spectrum obtainedcorresponding to form V of the laevorotatory enantiomer of modafinil(Diffractometer: Bruker GADDS).

FIG. 15 shows the powder X-ray diffraction spectrum obtainedcorresponding to the acetic acid solvate of the laevorotatory enantiomerand the dextrorotatory enantiomer of modafinil respectively(Diffractometer: Bruker GADDS).

FIG. 16 shows the powder X-ray diffraction spectrum obtainedcorresponding to the amorphous form of the laevorotatory enantiomer anddextrorotatory enantiomer of modafinil respectively (Diffractometer:Bruker GADDS).

EXAMPLES Preparation of Crystalline Forms of the (−)-ModafinilEnantiomer and the (+)-Modafinil Enantiomer Respectively

General

The new crystalline forms of the enantiomers of modafinil have beencharacterised respectively by powder X-ray diffraction spectroscopy,which provides a unique digital signature characteristic of thecrystalline form investigated and can be used to distinguish it fromamorphous enantiomers of modafinil and any other crystalline form ofmodafinil enantiomers.

The X-ray diffraction data were measured:

-   -   the D5005 system as an X-ray powder diffractometer (Siemens AG,        Karlsruhe, Germany, Eva 5.0 data analysis method), with        nickel-filtered copper radiation at λ=1,540 Å (with an        accelerator speed of 40 KV, tube current 40 mA) and rotation of        the sample during measurement (angle: 3 to 40° [2 theta] at a        rate of 0.04° [2 theta].s⁻¹, the step size being 0.04°,        preparation of the sample with a preferential orientation).    -   a Miniflex Rigaku (Elexience) system as an X-ray powder        diffractometer using chromium radiation, an accelerator speed of        30 KV, a tube current of 15 mA and rotation of the sample during        measurement (angle: 3 to 80° [2 theta] at a rate of 0.05° [2        theta]. s⁻¹, the step size being 0.1°, preparation of the sample        with a preferential orientation).    -   Using a GADDS system as a X-ray powder diffractometer (Bruker,        the Netherlands), equipped with a <<Hi-Star area>> detector and        equipped for the analysis of plates with 96 wells. The analyses        were performed at ambient temperature using CuK_(alpha) copper        radiation in the region of 2 theta angles between 3 and 42°. The        diffraction spectrum for each well is collected between two        domains of the value for the 2 theta angle (3°≦2 Theta≦21° and        19°≦2 Theta≦42°) with an exposure time of between 50 and 250        seconds.

Of course the intensity values can vary in relation to samplepreparation, the assembly and the measuring instruments. The 2 thetameasurement can also be affected by variations associated with themeasuring instruments, so the corresponding peaks can vary from ±0.04°to ±0.2° according to the equipment. Also a person skilled in the artwill appreciate having available the interplanar spacings whichconstitute essential data for diffraction spectra. The interplanarspacings are calculated using Bragg's relationship [(2d sin theta=nλ, inwhich d=the interplanar spacing (Å), λ=the wavelength of the copperradiation, theta=the angle of rotation of the crystal (in degrees)] whenthis relationship is satisfied.

Examples 1 to 10 Preparation of Form I of (−)-Modafinil AND(+)-Modafinil Respectively Example 1

-   -   a) Enantiomer I of modafinil was dissolved in polar solvents:        methanol, absolute ethanol, absolute ethanol containing 3% of        water, ethanol denatured with toluene (2.5%) and containing 3%        of water, and water under reflux under the experimental        conditions detailed in Table 1.

TABLE 1 Quantity of I-modafinil Volume of solvent Solvent (g) (ml) Yield% Methanol 8.37 ≦50 63 Absolute ethanol 7.85 115 56 Absolute ethanol +3% 5 70 54 of water Ethanol denatured with 5 70 56 toluene + 3% of waterWater 5 ≧400 88

After rapid cooling by quenching in a water and ice bath for 30 minutesthe medium was filtered and then dried in a stove at 35° C. Thecrystallised product was identified by its powder X-ray diffractionspectrum as being the polymorph of form I of the I-enantiomer ofmodafinil.

b) Enantiomer d of modafinil (555 g), treated under the sameexperimental conditions as example 1a in a mixture of ethanol denaturedwith toluene (2 L) and water (0.1 L), crystallised in polymorphic form Ias identified by its powder X-ray diffraction spectrum with a yield of91%.

Example 2 Recrystallisation from Acetone

a) 2 g of (−)-modafinil were suspended in acetone (20 ml) in athree-necked flask fitted with a condenser, a thermometer and a stirrer.The mixture was heated under reflux. The reaction mixture was stirredfor 30 minutes at approximately 56° C. until the (−)-modafinil wascompletely dissolved. The solution was then cooled slowly at a rate of−0.5° C./min to 10° C. with stirring. The reaction mixture was filtered,and the solid obtained was dried to yield the I form of (−)-modafinilidentified by its X-ray diffraction spectrum. Yield 62%.

b) The same experimental conditions applied to (+)-modafinil led to theacquisition of an identical X-ray diffraction spectrum.

Example 3 Recrystallisation from Methanol

a) 1 g of (−)-modafinil was added to 7 ml of methanol and heated underreflux until the (−)-modafinil was completely dissolved. The reactionmixture was precipitated by adding 6 ml of water at 1° C. The suspensionwas stirred continuously for 1 minute and then filtered on sinteredglass (No. 3). The solid isolated was dried to yield form I of(−)-modafinil identified by its X-ray diffraction spectrum. Yield 55%.

b) The same experimental conditions applied to (+)-modafinil led to theacquisition of an identical X-ray diffraction spectrum.

Example 4 Recrystallisation from Methanol (2^(nd) Example)

a) 2.5 g of (−)-modafinil were added to 90 ml of methanol and heatedunder reflux until the (−)-modafinil was completely dissolved. The clearsolution was added to 200 ml of water at 1° C. and kept stirred for 10min. The reaction mixture was filtered and the recovered solid was driedto yield form I of (−)-modafinil identified by its X-ray diffractionspectrum. Yield 78%.

b) The same experimental conditions applied to (+)-modafinil led to theacquisition of an identical X-ray diffraction spectrum.

Example 5 Recrystallisation from 1-4 Dioxan

a) 20 mL of 1-4 dioxan were placed in a 50 mL flask and placed underreflux. 2 g of (−)-modafinil were added in order to achieve saturation;stirring was provided by a magnetic bar (300 rpm). The whole was cooledafter total dissolution of the (−)-modafinil using a cooling gradient of−0.5° C./min down to 20° C. The crystals obtained were filtered onsintered glass and identified as being form I by its X-ray diffractionspectrum. Yield 51%.

b) The same experimental conditions applied to (+)-modafinil led to theacquisition of an identical X-ray diffraction spectrum.

Example 6 Recrystallisation from a Mixture of Ortho, Meta and ParaXylene

a) 180 mL of a mixture of ortho, meta and para xylene were placed in a250 mL flask and placed under reflux. 0.5 g of (−)-modafinil were addedto achieve saturation; stirring was provided by a magnetic bar (300rpm). The whole was cooled after total dissolution of the (−)-modafinilusing a cooling gradient of −0.5° C./min down to 15° C. The crystalsobtained were filtered on sintered glass and identified as being form Iby its X-ray diffraction spectrum. Yield 26%.

b) The same experimental conditions applied to (+)-modafinil led to theacquisition of an identical X-ray diffraction spectrum.

Example 7 Recrystallisation from Ethyl Acetate

a) 100 mL of ethyl acetate were placed in a 250 mL flask and placedunder reflux; 2 g of (−)-modafinil were added in order to achievesaturation; stirring was provided by a magnetic bar (300 rpm). The wholewas cooled after total dissolution of the (−)-modafinil using a coolinggradient of −0.5° C./min down to 20° C. The crystals obtained werefiltered on sintered glass and identified as being form I by its X-raydiffraction spectrum. Yield 66%.

b) (+)-modafinil (3 g) was dissolved in ethyl acetate (100 ml) underreflux. After cooling by quenching in a water and ice bath for 30minutes, the medium was filtered and then dried in a stove at 50° C.under vacuum. The crystallised product was identified by its powderX-ray diffraction spectrum as being the polymorph of form I of(+)-modafinil.

Example 8 From Other Polymorphic Forms

a) CRL 40982 form IV (0.5 g) and CRL 40982 form II (0.5 g) yielded formI by heating to 100° C.

Furthermore the pure form I of (−)-modafinil can be prepared by takingup a mixture of (−)-modafinil form I (0.5 g) and form II (0.5 g) andform III (0.5 g) in acetone (20 ml) for a sufficient time to achievecomplete conversion (3 days).

In the two procedures form I was identified by its powder X-raydiffraction spectrum.

b) The use of (+)-modafinil (CRL 40983) under the same conditionsyielded the same results.

Example 9 From Acetonitrile Solvate

a) 1 g of acetonitrile solvate of (−)-modafinil heated to 100° C. for 8hours converted into a white solid identified as being (−)-modafinilform I by its powder X-ray diffraction spectrum.

b) The use of (+)-modafinil (CRL 40983) under the same conditions led tothe same results.

Example 10 From Monodimethyl Carbonate Solvate

a) 1 g of the monodimethyl carbonate solvate of (−)-modafinil heated to110° C. for 16 hours converted into a white solid identified as being(−)-modafinil form I by its powder X-ray diffraction spectrum.

b) The use of (+)-modafinil (CRL 40983) under the same conditions led tothe same results.

Examples 11 to 12 Preparation of Form II (CRL 40982 Form II) of(−)-Modafinil and (CRL 40983 Form II) of (+)-Modafinil RespectivelyExample 11 through Rapid Cooling

a) Modafinil enantiomer I was dissolved under reflux in the solvents:ethyl acetate, isopropanol, n-propanol and ethanol denatured withtoluene (2.5%), according to the experimental conditions detailed inTable 2.

TABLE 2 Quantity of Volume of solvent Solvent I-modafinil (g) (ml) Yield% Ethyl acetate 6.33 385 53 Isopropanol 8 110 69 n-propanol 7.85 65 70Ethanol denatured 5 80 54 with toluene (2.5%)

After cooling by quenching in a water and ice bath for 30 minutes, themedium was filtered and then dried in a stove at 35° C. In eachexperimental procedure the crystallised product was identified by itspowder X-ray diffraction spectrum as being the form II polymorph (CRL40982 form II) of the I-enantiomer of modafinil.

b) The d enantiomer of modafinil (3.02 g) was dissolved in 100 ml ofisopropanol under reflux and then cooled by quenching in a water and icebath for minutes, filtered and dried under vacuum in a stove at 50° C.Under these experimental conditions (+)-modafinil crystallised intopolymorphic form II (CRL 40983 form II) identified by its powder X-raydiffraction spectrum.

Example 12 By Cooling from Isopropanol

a) 100 mL of isopropanol was placed in a 250 mL flask which was placedunder reflux and then 3 g of (−)-modafinil were added so as to achievesaturation, the mixture was stirred using a magnetic bar (300 rpm).After total dissolution of the (−)-modafinil the solution was slowlycooled to 20° C. at a cooling gradient of _−0.5° C./min. The crystalsobtained were filtered on sintered glass. The crystallised product wasidentified by its powder X-ray diffraction spectrum as being the form IIpolymorph (CRL 40982 form II) of the I-enantiomer of modafinil. Yield42%.

b) The same experimental conditions applied to (+)-modafinil led to theacquisition of an identical X-ray diffraction spectrum.

Example 13 Preparation of Form III (CRL 40982 Form III) of (−)-Modafiniland (CRL 40983 Form III) of (+)-Modafinil Respectively Example 13 BySlow Cooling from Acetone

a) The I enantiomer of modafinil (5 g) was dissolved under reflux in 90ml of acetone. After rapid cooling by quenching in a water and ice bathfor 30 minutes the medium was filtered and then dried in a stove at 35°C. The crystallised product was identified by its powder X-raydiffraction spectrum as being the form III polymorph of I-enantiomer ofmodafinil. Yield 61%.

b) The same experimental conditions applied to (+)-modafinil led to theacquisition of an identical X-ray diffraction spectrum.

Examples 14 to 16 Preparation of Form IV (CRL 40982 Form IV) of(−)-Modafinil and (CRL 40983 Form III) of (+)-Modafinil RespectivelyExample 14 Recrystallisation from Chloroform

a) 20 mL of chloroform was placed in a 50 mL flask and heated underreflux. 1.5 g of (−)-modafinil were added so as to achieve saturation;stirring was provided by a magnetic bar (300 rpm). The whole was slowlycooled after total dissolution of the (−)-modafinil at a coolinggradient of −0.5° C./min down to 20° C. The crystals obtained werefiltered on sintered glass and identified as being (−)-modafinil form IVby its powder X-ray diffraction spectrum.

b) The same experimental conditions applied to (+)-modafinil led to theacquisition of an identical X-ray diffraction spectrum.

Example 15 Recrystallisation from Methylethylketone

a) 100 mL of methylethylketone was placed in a 250 mL flask and heatedunder reflux. 2 g of (−)-modafinil were added so as to achievesaturation; stirring was provided by a magnetic bar (300 Rpm). The wholewas slowly cooled after total dissolution of the (−)-modafinil at acooling gradient of −0.5° C./min down to 20° C. The crystals obtainedwere filtered on sintered glass and identified as being (−)-modafinilform IV by its powder X-ray diffraction spectrum.

b) The same experimental conditions applied to (+)-modafinil led to theacquisition of an identical X-ray diffraction spectrum.

Example 16 Recrystallisation from Tetrahydrofuran

20 mL of tetrahydrofuran was placed in a 50 mL flask which was heatedunder reflux. 1 g of (−)-modafinil was added so as to achievesaturation; stirring was provided by a magnetic bar (300 Rpm). The wholewas slowly cooled after total dissolution of the (−)-modafinil with acooling gradient of −0.5° C./min down to 10° C. The crystals obtainedwere filtered on sintered glass and identified as being (−)-modafinilform IV by its powder X-ray diffraction spectrum.

Examples 17 and 17B Preparation of Form V (CRL 40982 Form V) Of(+)-Modafinil and (CRL 40983 Form V) of (+)-Modafinil Respectively

Operating Procedure for Examples 17 and 17 b

A methanol solution of the d enantiomer of modafinil (150 mg/ml) wasdistributed over a 96-well plate and then the methanol was evaporatedunder slight vacuum before adding 25 μl of various solvents(concentration=3.75 mg/25 μL of solvent) at ambient temperature. Themulti-well plates were made of stainless steel (316 L) and each sealedwell contained a total volume of 50 μL. The plate was heated to aninitial temperature of 60° C. with a temperature gradient of 4.8°C./min. After 30 minutes the plate was cooled slowly (−0.6° C./min) orrapidly (−300° C./min) until a final temperature of 3° C. was achieved,and it was then held at that final temperature for a minimum of 1 houror a maximum of 48 hours. The solvent was evaporated under vacuum(nitrogen atmosphere) and the crystallised product was analysed.

Example 17 Recrystallisation from 2-Propanone

d-modafinil crystallised from 2-propanone in accordance with theoperating conditions above by applying slow cooling (−0.6° C./min) andholding the temperature at 3° C. for 1 hour. The crystals wereidentified as being (+)-modafinil form V (CRL 40983 form V) by itspowder X-ray diffraction spectrum.

Example 17b Recrystallisation from Tetrahydrofuran (THF)

d-modafinil crystallised from THF in accordance with the operatingconditions above by applying rapid cooling (−300° C./min) and holdingthe temperature at 3° C. for 1 hour. The crystals were identified asbeing (+)-modafinil form V (CRL 40983 form V) by its powder X-raydiffraction spectrum.

Examples 18 to 19 Preparation of (−)-Modafinil Solvates and of(+)-Modafinil Example 18 Preparation of the Dimethyl Carbonate Solvateof (−)-Modafinil

a) 20 ml of dimethyl carbonate were added to 2 g of (−)-modafinil andrefluxed. The reaction mixture was stirred for 10 minutes until the(−)-modafinil completely dissolved. The solution was cooled slowly(−0.5° C./min) down to 10° C. with stirring. The reaction mixture wasthen filtered through sintered glass (No. 3). Analysis of the dimethylcarbonate solvate of modafinil yielded a mass of approximately 24%starting from around 50° C. down to 110° C. The stoichiometry of thedimethyl carbonate solvate is therefore 1-1. This is therefore a truesolvate, identified as being the dimethyl carbonate solvate of(−)-modafinil by its powder X-ray diffraction spectrum. Yield 88%.

b) The same experimental conditions applied to (+)-modafinil led to theacquisition of an identical X-ray diffraction spectrum.

Example 19 Preparation of the Acetonitrile Solvate of (−)-Modafinil

a) Crystals of polymorphic form I of (−)-modafinil were suspended inacetonitrile for 3 days at 20° C. The solid recovered was identified asan acetonitrile solvate by X-ray diffraction. The solvate correspondedto a true solvate having a stoichiometry of 1-1, identified as being theacetonitrile solvate of (−)-modafinil by its powder X-ray diffractionspectrum. Yield 92%.

b) The same experimental conditions applied to (+)-modafinil led to theacquisition of an identical X-ray diffraction spectrum.

Example 20 Preparation of the Acetic Acid Solvate

a) 75 mg of d or l-modafinil were suspended in acetic acid in Minimax 10reactors in order to achieve a concentration of 15% (weight/volume). Thecrystallisation medium, which was constantly stirred, was raised to aninitial temperature of 60° C. or 80° C. using a temperature gradient of3° C./min. After 30 minutes the medium was cooled slowly (−0.6° C./min)or rapidly (−300° C./min) until a final temperature of 3° C. wasobtained, and was then held at this final temperature for a minimum of 1hour or a maximum of 48 hours. Under these experimental conditions theacetic acid solvate was obtained and identified by its powder X-raydiffraction spectrum.

b) The same experimental conditions applied to (+)-modafinil led to theacquisition of an identical X-ray diffraction spectrum.

Example 21 Preparation of the Amorphous Form of (−) and of (+)-Modafinil

The solvate of (−) or (+)-modafinil obtained in example 20 was convertedinto the amorphous form by heating at 120° C. for 3 hours. The powderX-ray diffraction spectrum obtained is shown in FIG. 16.

Examples 22 to 29 Resolution of (±)-Modafinil Acid by PreferentialCrystallisation

Using the AS3PC Method in Ethanol

-   -   Conditions associated with the equilibria        -   Solubility of the racemic mixture in ethanol:

Temperature (° C.) 10.0 20.0 30.0 Solubility by mass (%) 3.0 4.1 5.96

-   -   -   Solubility of the pure (+)-antipode=1.99% at 20° C.; ratio            α=2.06        -   Coordinates of point L=Concentration: 5.96%. temperature:            30° C.

    -   Change in T_(HOMO) with enantiomer excess=(racemic        mixture/(solvent+racemic mixture))=5.96%=constant

Enantiomer excess 0 3.94 7.66 11.1 T_(HOMO) (° C.) T_(L) = 30 32.4 34.536.3

-   -   Conditions associated with the kinetics

By adjusting T_(B) to be closer to T_(L) approximately 40% of the finalharvest in the form of fine crystals can be thus obtained at the startof the experiment, and then only 60% of the expected final mass has tobe produced. This operation is easy to carry out when the Z ratio issufficiently high (equal to or greater than 0.8 per percentageenantiomer excess).

In the case of modafinil acid, crystallisation is carried out correctly.

$Z = {\left\lbrack \frac{\left( T_{HOMO} \right)}{{e}.e} \right\rbrack_{{( \pm )}{constant}} = {Z = {\left\lbrack \frac{\left( T_{HOMO} \right)}{{e}.e} \right\rbrack_{{TL}\; {constant}} = \frac{5}{9}}}}$

Temperature T_(B1)=33.5° C. and T_(B2)=31.5° C. Temperature T_(F)=17° C.

Cooling function=T=f(t)

Type I cooling function Temperature (° C.) 33.5 17 17 t (min) 0 60T_(Filtration)

Type II cooling function Temperature (° C.) 31.5 17 17 t (min) 0 60T_(Filtration)

In the two cases in point, from TB1 or TB2 the cooling function is alinear segment:

T₁=33.5-0.275 t (Type I)

T₂=31.5-0.24167 t (Type 2)

followed by a plateau at 17° C.

Example 22 Resolution of (±)-Modafinil Acid by the AS3PC Method at the35 cc Scale in Ethanol

Initial Conditions

Enantiomer excess=11%

Mass of solvent Mass (±) (g) Mass (+) (g) Cooling function 38.38 2.430.3 Type 1

Duration of the plateau at T_(B1) or T_(B2)=30 minutes.

Stirring speed=200 rpm

Results

Mass of the pure antipode No. (g) Optical purity (%) 1 0.61 (+) 90.7 20.65 (−) 89.4 3 0.68 (+) 90.5 4 0.64 (−) 90.6 5 0.65 (+) 88.8 6 0.72 (−)91.5 7 0.71 (+) 92.8

-   -   Mean mass of the crystals of the pure antipode=0.66 g    -   Average optical purity=90.6%

Example 23 Resolution of (±)-Modafinil Acid by the AS3PC Method on aScale of 400 cc in Ethanol

Initial Conditions

Initial enantiomer excess=11%

Mass of solvent Mass (±) (g) Mass (+) (g) Cooling function 511 32.423.99 Type IStirring speed=200 rpm

Results

Mass of the pure antipode No. (g) Optical purity (%) 1 8.41 (+) 89.4 28.69 (−) 90.7 3 8.57 (+) 89.8

-   -   Mean mass of the crystals of the pure antipode=8.55 g    -   Average optical purity=89.63%

Example 24 Resolution of (±) Modafinil Acid by the AS3PC Method on a 2Litre Scale in Ethanol

Initial Conditions

Initial enantiomer excess=11.1%

Mass of solvent Mass (±) (g) Mass (+) (g) Cooling function 1874 118.414.84 Type I

Results

Mass of the pure antipode No. (g) Optical purity (%) 1 32.1 (+) 89.1 232.3 (−) 90.3 3 32.5 (+) 91.2 4 32.9 (−) 89.7 5 33.1 (+) 90.3 6 32.7 (−)90.7 7 32.9 (+) 90.6

-   -   Mean mass of the crystals of the pure antipode=32.6 g    -   Average optical purity=90.3%

Example 25 Resolution of (±) Modafinil Acid by the AS3PC on a 10 LitreScale in Ethanol

Initial Conditions

Initial enantiomer excess=11.7%

Mass of solvent Mass (±) (g) Mass (+) (g) Cooling function 6481 40851.32 Type I or IIStirring speed=200 rpm throughout the procedure using an Impeller®moving stirrer.

Results

Mass of the pure antipode Optical purity Cooling No. (g) (%) Cyclelength function 1 (+) 121.9 90.5 103 I 2 (−) 121.1 92.2 104 I 3 (+)137.6 91.3 83 II 4 (−) 134.7 90.8 84 II 5 (+) 135.1 90.6 83 II 6 (−)134.5 91.2 82 II

-   -   Mean mass of the crystals of the pure antipode=130.8 g    -   Average optical purity=89.9%

Using the AS3PC Method in 2-Methoxyethanol

-   -   Conditions associated with the equilibria        -   Solubility of the racemic mixture in 2-methoxyethanol:

Temperature (° C.) 10.0 20.0 30.0 40.0 Solubility by mass (%) 7.4 8 13.516

-   -   -   Solubility of the pure (+) antipode=4% at 20° C. ratio            α=2.53        -   Coordinates of point L=Concentration: 16%. temperature:            39.4° C.

    -   Change in T_(HOMO) with enantiomer excess=(racemic        mixture/(solvent+racemic mixture))=16%=constant

Enantiomer excess 0 4% 6% 8% T_(HOMO) (° C.) T_(L) = 39 44 46 48

Example 26 Resolution of (±)-Modafinil Acid in 2-Methoxyethanol by theAS3PC Method on a 10 Litre Scale

Initial Conditions

Enantiomer excess=10%

Initial temperature T_(B): 41° C.

Filtration temperature T_(F): 30° C.

Linear temperature gradient from 41° C. to 30° C. in 1 hour

Mass of solvent Mass (±) (g) Mass (+) (g) 8000 g 1523 132

Stirring speed=200 rpm

Results

Mass of the pure antipode Optical No. (g) purity (%) 1 269.86 (+) 100 2300 (−) 97 3 348.68 (+) 100 4 369.2 (−) 99.97 5 413.97 (+) 100 6 453.2(−) 95.5 7 423.8 (+) 98 8 456 (−) 99.7 9 494.6 (+) 99.3 10 485.4 (−) 10011 517 (+) 92 12 487.97 (−) 95.9 13 471.24 (+) 99.5

-   -   Mean mass of the crystals of the pure antipode=422.4 g    -   Average optical purity=98.2%

Using the AS3PC Method in Methanol

-   -   Conditions associated with the equilibria        -   Solubility of the racemic mixture in methanol:

Temperature (° C.) 10.0 20.0 30.0 40.0 Solubility by mass (%) 7.4 9.713.9 25.7

-   -   -   Solubility of the pure (+) antipode=4.9% at 20° C. ratio            α=2.53        -   Coordinates of point L=Concentration: 25.6%. temperature:            46.5° C.

    -   Change in T_(HOMO) with enantiomer excess=(racemic        mixture/(solvent+racemic mixture))=25.7%=constant

Enantiomer excess 0 4% 6% 8% 10% T_(HOMO) (° C.) T_(L) = 45 50 52 53 54

Example 27 Resolution of (±)-Modafinil Acid by the AS3PC Method on a 1Litre Scale in Methanol

Experimental Conditions

Enantiomer excess=10%

Initial temperature T_(B): 46.5° C.

Filtration temperature T_(F): 30° C.

Temperature gradient: linear from 39.4° C. to 18° C. for 1 hour

Mass of solvent Mass (±) (g) Mass (+) (g) 1450 g 501.5 55.7

Stirring speed=230 rpm

Results

Mass of the pure antipode Optical No. (g) purity (%) 1 107.1 (+) 99.7 290.9 (−) 78.2 3 137.1 (+) 72.7 4 125.5 (−) 84.1 5 95.9 (+) 94.0 6 91.6(−) 88.6 7 87.0 (+) 85.7 8 92.2 (−) 88.1 9 107.0 (+) 104.2 10 130.6 (−)120.7 11 159.9 (+) 111.0 12 123.3 (−) 113.8 13 133.0 (+) 130.3 14 143.0(−) 134.7 15 139.2 (+) 128.5 16 159.4 (−) 127.5 17 114.0 (+) 111.5 18123.4 (−) 120.9 19 180.6 (+) 99.3 20 114.2 (−) 110.9 21 123.1 (+) 120.622 118.4 (−) 115.0 23 140.1 (+) 135.9 24 186.2 (−) 118.6 25 157.1 (+)106.8 26 121.2 (−) 102.2 27 126.5 (+) 122.5 28 106.6 (−) 99.0

-   -   Mean mass of the crystals of the pure antipode=108 g    -   Average optical purity=87.5%

Using the SIPC Method in Ethanol

Conditions associated with the equilibria (see AS3PC method)

Example 28 Resolution of (±) Modafinil Acid by the SIPC Method on a 2Litre Scale with Seeding at the End of Cooling in Ethanol

Initial Conditions

Initial enantiomer excess=11.8%

-   -   Temperature at which the starting mixture is a homogeneous        solution T_(D)=40° C.

Mass of solvent Mass (±) (g) Mass (+) (g) Cooling function 1874 118.414.84 20 min from 40° C. to 17° C. = seeding temperature

-   -   -   Time (plateau) at T_(F) before adding the seeds=0 minutes        -   Mass of seeds=1%        -   Crystallisation time=fastest possible cooling by quenching            Stirring speed=200 rpm throughout the procedure using an            Impeller® mobile stirrer.

Results

Mass of the pure antipode No. (g) Optical purity (%) 1 30.9 (+) 90.4 231.5 (−) 90.7 3 31.3 (+) 91.4 4 31.2 (−) 90.9 5 31.6 (+) 91.5

-   -   Mean mass of the crystals of the pure antipode=31.28 g    -   Average optical purity=91%

Example 29 Resolution of (±)-Modafinil Acid by the S3PC Method on a 2Litre Scale with Seeding during Cooling in Ethanol

Initial enantiomer excess 11.14%

Mass of solvent Mass (±) (g) Mass (+) (g) Cooling function 1874 118.414.84 20 min from 40° C. to 17° C.

-   -   Seeding temperature=29° C.    -   Seed mass=1%    -   Crystallisation time=the fastest possible cooling by quenching        Stirring speed=200 rpm throughout the procedure using an        Impeller® mobile stirrer.

Results

Optical purity (%) No. Mass before purification 1 25.2 (+) 84.5 2 24.9(−) 85.6 3 25.6 (+) 84.6 4 25.2 (−) 85.3 5 24.9 (+) 85.8

-   -   Mean mass of the crystals of the pure antipode=25.2 g    -   Average optical purity=85.2%

Examples 30 to 32 Conversion of the Optical Enantiomers of ModafinilAcid to Alkyl Ester

This stage is illustrated through the use of (−)modafinil acid.

Examples 30 to 31 Esterification of (−)-Modafinil Acid Example 30 In thePresence of Dimethylsulphate

3.3 litres of acetone, 0.6 litres of water, 349 g of Na₂CO₃ (3.29moles), 451 g of (−)-modafinil acid (1.64 moles) were placed in a 10litre flask and heated to achieve reflux. Then 330 ml of dimethylsulphate (3.29 moles) were run in over half an hour. Reflux wascontinued for one hour and then it was allowed to cool to ambienttemperature in 20 hours.

The medium was then poured on to 6.6 kg of ice. Crystallisation wasimmediate and after 3 hours additional stirring filtration yielded awhite precipitate which was washed in 6 litres of water.

This product was taken up again in 6 litres of water and again filtered.The precipitate was dried under vacuum at 35° C. and in this way 436.3 gof methyl ester were obtained (Yield=92.3%).

Example 31 In the Presence of Methyl Chloroformate

-   -   100 g of (−)-modafinil acid (0.36 mole) and 21.6 ml of        triethylamine (0.36 mole) were added to 450 ml of methanol. 30        ml of methyl chloroformate 0.36 mole) were progressively poured        onto the solution obtained after dissolution of the salt.

Pouring was carried out over 15 minutes increasing from 28° C. to 35° C.(release of CO₂). This was stirred for 2 hours and poured onto piledice+water (500 g/500 ml).

The ester crystallised out; after filtering and drying 94.5 g of esterwas obtained.

(Yield=90.1%).

Example 32 Ammonolysis of the Alkyl Ester of Optically Active ModafinilAcid

1.63 litres of methanol denatured with toluene, 0.1 litres of water and425.1 g of methyl ester (1.474 moles) were placed in a 4 litre doublejacket reactor.

The temperature was raised to 30° C. and bubbling of ammonia was begunmaintaining this temperature. The operation lasted 1 hour and 45 minutesand the mass of ammonia introduced was 200 g. Stirring was maintainedfor 21 hours 30 minutes, and then it was cooled with the temperaturebeing set to 0° C.

The medium was then filtered on No. 3 sintered glass and 57.2 g wasobtained straight away, together with a filtrate which was evaporated todryness. The residue was taken up in 1.2 litres of ethanol denaturedwith toluene and after filtration a second amount of 308.6 g wasobtained.

First Crystallisation:

The two amounts were pooled and recrystallised in 1.83 litres of ethanoldenatured with toluene. Hot filtration yielded a filtrate which whencooled yielded a product which was filtered and dried under vacuum at30° C. 162.2 g of a white product was obtained.

Second Crystallisation

These 162.2 g were mixed with 810 ml of ethanol denatured with tolueneand heated under reflux to achieve complete dissolution. This was thenallowed to crystallise by cooling with ice and then filtered through No.4 sintered glass and dried under vacuum at 30° C. 147.3 g (−)-modafinil(CRL 40982) was obtained.

Yield=36.6%.

Characteristics:

Rotation power=−18.6 (4.9% solution in methanol)

Melting point=163° C.

Examples 33 to 34 Crystalline Structures Example 33 Structure ofModafinil Acid

Modafinil crystals were obtained from acetone. This phase has thefollowing characteristics:

-   -   Hexagonal P3₁ or P3₂ depending upon the enantiomer, the        modafilil is therefore a conglomerate,    -   a=9.55, b=9.55, c=13.14 Å    -   α=90,000, β=90,000, γ=120,000°

The diffraction intensities were measured using an automatic SMART APEX(Brucker) diffractometer at 20° C.

The structure was resolved using the set of Saintplus, Sadabs, Shelxssoftware packages.

The unusual nature of this spatial group in the case of chiral organicmolecules must be emphasised.

The pattern repeats three times in the crystal lattice, so again Z=1.The molecules are linked together by hydrogen bonds via the acid andsulphoxide groups. It may be commented that the strongest interactions(the hydrogen bonds) wrap around the ternary helical axis along thecrystallographic direction z.

Example 34 Structure of (−) and (+)-Modafinil Form I

The crystalline structure of (+)-modafinil form I, identified as beingidentical to that of (−)-modafinil form I, was determined. It has thefollowing properties

-   -   Crystalline system=monoclinic,    -   Spatial group=P2₁    -   a=5.6938, b=26.5024, c=9.3346 Å    -   β=105.970°

The diffraction intensities were measured using an automatic SMART APEX(Brucker) diffractometer at 20° C.

1. A polymorphic form of (−)-modafinil that produces a powder X-raydiffraction spectrum comprising intensity peaks corresponding tointerplanar spacings of about 9.45, 7.15, 5.13, 4.15 and 3.67 Å.
 2. Apolymorphic form of (−)-modafinil that produces a powder X-raydiffraction spectrum comprising reflections at about 9.36, 12.38, 17.29,21.40 and 24.25 degrees 2θ.
 3. A composition consisting essentially of apolymorphic form of (−)-modafinil that produces a powder X-raydiffraction spectrum comprising intensity peaks corresponding tointerplanar spacings of about 9.45, 7.15, 5.13, 4.15 and 3.67 Å.
 4. Acomposition consisting essentially of a polymorphic form of(−)-modafinil that produces a powder X-ray diffraction spectrumcomprising reflections at about 9.36, 12.38, 17.29, 21.40 and 24.25degrees 2θ.
 5. The polymorphic form according to claims 1 or 2, whereinsaid polymorphic form is substantially free of Form I (−)-modafinil. 6.The polymorphic form according to claims 1 or 2, wherein saidpolymorphic form is substantially free of Form II (−)-modafinil.
 7. Thepolymorphic form according to claims 1 or 2, wherein said polymorphicform is substantially free of Form IV (−)-modafinil.
 8. The polymorphicform according to claims 1 or 2, wherein said polymorphic form issubstantially free of Form V (−)-modafinil.
 9. The polymorphic formaccording to claims 1 or 2, wherein said polymorphic form issubstantially free of Forms I, II, IV and V (−)-modafinil.
 10. Thepolymorphic form according to claims 1 or 2, wherein said polymorphicform is substantially free of other polymorphic forms of (−)-modafinil.11. The composition according to claims 3 or 4, wherein said compositionis substantially free of Form I (−)-modafinil.
 12. The compositionaccording to claims 3 or 4, wherein said composition is substantiallyfree of Form II (−)-modafinil.
 13. The composition according to claims 3or 4, wherein said composition is substantially free of Form IV(−)-modafinil.
 14. The composition according to claims 3 or 4, whereinsaid composition is substantially free of Form V (−)-modafinil.
 15. Thecomposition according to claims 3 or 4, wherein said composition issubstantially free of Forms I, II, IV and V (−)-modafinil.
 16. Thecomposition according to claims 3 or 4, wherein said composition issubstantially free of other polymorphic forms of (−)-modafinil.
 17. Anacetic acid solvate of (−)-modafinil.
 18. A composition comprising theacetic acid solvate of (−)-modafinil of claim
 17. 19. A compositionconsisting essentially of the acetic acid solvate of (−)-modafinil ofclaim
 17. 20. A composition comprising the acetic acid solvate of(−)-modafinil of claim 17, wherein said composition is substantiallyfree of other polymorphic forms of (−)-modafinil.
 21. A pharmaceuticalcomposition comprising one or more pharmaceutically acceptableexcipients and the acetic acid solvate of (−)-modafinil of claim
 17. 22.A pharmaceutical composition comprising one or more pharmaceuticallyacceptable excipients and an active ingredient consisting essentially ofthe acetic acid solvate of (−)-modafinil of claim
 17. 23. Apharmaceutical composition comprising one or more pharmaceuticallyacceptable excipients and a polymorphic form of (−)-modafinil as definedin claim
 1. 24. A pharmaceutical composition comprising one or morepharmaceutically acceptable excipients and a polymorphic form of(−)-modafinil as defined in claim
 2. 25. A process for preparing theacetic acid solvate of (−)-modafinil of claim 17, comprising the stepsof: (a) providing a solution of (−)-modafinil dissolved in hot aceticacid; (b) cooling the solution from step (a) to produce crystals; (c)filtering the crystals; (d) drying the crystals; and (e) obtaining thecrystals of said acetic acid solvate of (−)-modafinil, wherein theobtained crystals are substantially free of Form I (−)-modafinil.
 26. Aprocess for preparing the acetic acid solvate of (−)-modafinil of claim17, comprising the steps of: (a) providing a solution of (−)-modafinildissolved in hot acetic acid; (b) cooling the solution from step (a) toproduce crystals; (c) filtering the crystals; (d) drying the crystals;and (e) obtaining the crystals of said acetic acid solvate of(−)-modafinil, wherein the obtained crystals are substantially free ofForm II (−)-modafinil.
 27. A process for preparing the acetic acidsolvate of (−)-modafinil of claim 17, comprising the steps of: (a)providing a solution of (−)-modafinil dissolved in hot acetic acid; (b)cooling the solution from step (a) to produce crystals; (c) filteringthe crystals; (d) drying the crystals; and (e) obtaining the crystals ofsaid acetic acid solvate of (−)-modafinil, wherein the obtained crystalsare substantially free of Form IV (−)-modafinil.
 28. A process forpreparing the acetic acid solvate of (−)-modafinil of claim 17,comprising the steps of: (a) providing a solution of (−)-modafinildissolved in hot acetic acid; (b) cooling the solution from step (a) toproduce crystals; (c) filtering the crystals; (d) drying the crystals;and (e) obtaining the crystals of said acetic acid solvate of(−)-modafinil, wherein the obtained crystals are substantially free ofForm V (−)-modafinil.
 29. A process for preparing the acetic acidsolvate of (−)-modafinil of claim 17, comprising the steps of: (a)providing a solution of (−)-modafinil dissolved in hot acetic acid; (b)cooling the solution from step (a) to produce crystals; (c) filteringthe crystals; (d) drying the crystals; and (e) obtaining the crystals ofsaid acetic acid solvate of (−)-modafinil, wherein the obtained crystalsare substantially free of Forms I, II, IV and V (−)-modafinil.
 30. Aprocess for preparing the acetic acid solvate of (−)-modafinil of claim17, comprising the steps of: (a) providing a solution of (−)-modafinildissolved in hot acetic acid; (b) cooling the solution from step (a) toproduce crystals; (c) filtering the crystals; (d) drying the crystals;and (e) obtaining the crystals of said acetic acid solvate of(−)-modafinil, wherein the obtained crystals are substantially free ofother polymorphic forms of (−)-modafinil.
 31. A process for preparingthe acetic acid solvate of (−)-modafinil of claim 17, comprising thesteps of: (a) providing a solution of (−)-modafinil dissolved in hotacetic acid; (b) cooling the solution from step (a) to produce crystals;(c) filtering the crystals; (d) drying the crystals; and (e) obtainingthe crystals of said acetic acid solvate of (−)-modafinil.